Joseph Heitman is an American physician-scientist focused on research in genetics, microbiology, and infectious diseases. He is the James B. Duke Professor and Chair of the Department of Molecular Genetics and Microbiology at Duke University School of Medicine .
113-403: 4JT6 , 1AUE , 1FAP , 1NSG , 2FAP , 2GAQ , 2NPU , 2RSE , 3FAP , 4DRH , 4DRI , 4DRJ , 4FAP , 4JSN , 4JSP , 4JSV , 4JSX , 4JT5 , 5FLC 2475 56717 ENSG00000198793 ENSMUSG00000028991 P42345 Q9JLN9 NM_004958 NM_001386500 NM_001386501 NM_020009 NP_004949 NP_064393 The mammalian target of rapamycin ( mTOR ), also referred to as
226-540: A body mass index in excess of 30 kg/m (classified as obese). Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump ; hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma , whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma. Unlike the similarly named tacrolimus , sirolimus
339-467: A calcineurin inhibitor (such as tacrolimus ), and/or mycophenolate mofetil , to provide steroid-free immunosuppression regimens. Impaired wound healing and thrombocytopenia are possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains
452-570: A blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its pharmacokinetic (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both. Sirolimus
565-574: A clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus. A 2019 cohort study of nearly 10,000 lung transplant recipients in the US demonstrated significantly improved long-term survival using sirolimus + tacrolimus instead of mycophenolate mofetil + tacrolimus for immunosuppressive therapy starting at one year after transplant. Sirolimus can also be used alone, or in conjunction with
678-441: A core component of both complexes, mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation , cell motility , cell survival, protein synthesis , autophagy , and transcription . As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors . mTORC2 has also been implicated in
791-505: A distinct MTase, at C27 to yield rapamycin. The biosynthetic genes responsible for rapamycin synthesis have been identified. As expected, three extremely large open reading frames (ORF's) designated as rapA , rapB , and rapC encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively. The gene rapL has been established to code for a NAD+ -dependent lysine cycloamidase, which converts L- lysine to L- pipecolic acid (figure 4) for incorporation at
904-471: A long-term clinical study examining the effect of rapamycin on the longevity of dogs . Joseph Heitman Joseph Heitman grew up in southwestern Michigan and attended Portage Northern High School . He completed a dual Bachelor of Science – Master of Science program in chemistry and biochemistry at the University of Chicago from 1980 to 1984. There he began his research career, working in
1017-460: A manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1). mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect
1130-405: A mating partner, as well as sexual reproduction and recombination involving cell-cell fusion between individuals of the same mating type followed by meiosis and sporulation. Studies conducted in parallel defined and illuminated evolution and function of fungal mating-type loci, illustrating parallels with sex chromosome evolution of plants and animals, including the discovery and characterization of
1243-434: A more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin. The mTORC2 signaling pathway is less defined than the mTORC1 signaling pathway. The functions of the components of the mTORC complexes have been studied using knockdowns and knockouts and were found to produce
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#17327720886751356-593: A new medical treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation. Hence, sirolimus is ideal for "proliferative" vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway as an antiproliferative agent. Sirolimus has been used as
1469-500: A possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade. In 1991, calcineurin was identified as the target of FKBP12-FK506. That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993, followed by studies in 1994 when several groups, working independently, discovered
1582-430: A related compound, everolimus , increased elderly patients' immune response on an intermittent dose. This led to many in the anti-aging community self-experimenting with the compound. However, because of the different biochemical properties of sirolimus, the dosing is potentially very different from that of everolimus. Ultimately, due to known side-effects of sirolimus, as well as inadequate evidence for optimal dosing, it
1695-506: A sex-specific manner: limited rapamycin exposure enhanced male but not female lifespan, providing evidence for sex differences in sirolimus response. The results are further supported by the finding that genetically modified mice with impaired mTORC1 signalling live longer. Sirolimus has potential for widespread use as a longevity-promoting drug, with evidence pointing to its ability to prevent age-associated decline of cognitive and physical health. In 2014, researchers at Novartis showed that
1808-412: A similar amino acid sequence to mTOR in mammals. Role of mTOR in plants The TOR kinase complex has been known for having a role in the metabolism of plants. The TORC1 complex turns on when plants are living the proper environmental conditions to survive. Once activated, plant cells undergo particular anabolic reactions. These include plant development, translation of mRNA and the growth of cells within
1921-413: A simultaneous activation via galectin-9 (which also recognizes lysosomal membrane breach) of AMPK that directly phosphorylates and activates key components ( ULK1 , Beclin 1 ) of the autophagy systems listed above and further inactivates mTORC1, allows for strong autophagy induction and autophagic removal of damaged lysosomes. Additionally, several types of ubiquitination events parallel and complement
2034-805: A substrate of mTOR, specifically of mTORC2 , upregulates expression of the glycolytic enzyme PKM2 thus contributing to the Warburg effect . mTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in autism spectrum disorders. mTOR signaling intersects with Alzheimer's disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, findings demonstrate mTOR signaling hyperactivity in AD brains. For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR. mTOR signaling appears to be closely related to
2147-408: A topical treatment of angiofibromas with tuberous sclerosis complex (TSC). Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring. A retrospective review of English-language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug. The reports involved
2260-434: A total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease. Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations. Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation. In April 2022, sirolimus
2373-511: A transceptor for nitrogen source availability. Heitman's research program has also focused extensive studies on the pathogenesis, sexual cycle, and novel drug targets of the pathogenic fungus Cryptococcus . His group described a previously unknown form of sexual reproduction in Cryptococcus species, known as unisexual reproduction, which involves both selfing sexual reproduction (homothallism) of isolates grown on their own without
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#17327720886752486-452: A treatment for severe acute respiratory syndrome coronavirus 2 insofar as its immunosuppressive effects could prevent or reduce the cytokine storm seen in very serious cases of COVID-19. Moreover, inhibition of cell proliferation by rapamycin could reduce viral replication . Rapamycin can accelerate degradation of oxidized LDL cholesterol in endothelial cells , thereby lowering the risk of atherosclerosis. Oxidized LDL cholesterol
2599-458: Is a natural product and macrocyclic lactone . The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that
2712-421: Is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes , obesity , depression , and certain cancers . Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP 12. The FKBP12– rapamycin complex binds directly to
2825-408: Is a major contributor to atherosclerosis. As of 2016, studies in cells, animals, and humans have suggested that mTOR activation as process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease-modifying treatment. As of 2016 rapamycin had been tested in small clinical trials in people with lupus. Lymphatic malformation , lymphangioma or cystic hygroma,
2938-671: Is a negative regulator of autophagy in general, best studied during response to starvation, which is a metabolic response. During lysosomal damage however, mTOR inhibition activates autophagy response in its quality control function, leading to the process termed lysophagy that removes damaged lysosomes. At this stage another galectin , galectin-3 , interacts with TRIM16 to guide selective autophagy of damaged lysosomes. TRIM16 gathers ULK1 and principal components (Beclin 1 and ATG16L1 ) of other complexes (Beclin 1- VPS34 - ATG14 and ATG16L1 - ATG5 - ATG12 ) initiating autophagy , many of them being under negative control of mTOR directly such as
3051-719: Is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD. Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. Perhaps the same treatment may be useful in clearing Aβ deposits as well. Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases such as autoimmune lymphoproliferative syndrome (ALPS), multicentric Castleman disease , and post-transplant lymphoproliferative disorder (PTLD). mTORC1 activation
3164-637: Is a phenomenon also observed in humans. Active mTORC1 is positioned on lysosomes . mTOR is inhibited when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading bacteria , membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes), amyloid protein aggregates (see above section on Alzheimer's disease ) and cytoplasmic organic or inorganic inclusions including urate crystals and crystalline silica . The process of mTOR inactivation following lysosomal/endomembrane
3277-434: Is a serious complication associated with sirolimus therapy, especially in the case of lung transplants. The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway. The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease. There have been warnings about
3390-417: Is also metabolized primarily by the CYP3A4 enzyme. The bioavailabiliy of sirolimus is low, and the absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition. This is determined by taking
3503-412: Is an abnormal growth of lymphatic vessels that usually affects children around the head and neck area and more rarely involving the tongue causing macroglossia. LM is caused by a PIK3CA mutation during lymphangiogenesis early in gestational cell formation causing the malformation of lymphatic tissue. Treatment often consists of removal of the affected tissue via excision, laser ablation or sclerotherapy, but
mTOR - Misplaced Pages Continue
3616-867: Is an elected fellow or member of the Infectious Diseases Society of America (2003), American Society for Clinical Investigation (2003), American Academy of Microbiology (2004), American Association for the Advancement of Science (2004), the Association of American Physicians (2006), the American Academy of Arts and Sciences (2020) , the National Academy of Sciences (2021) , the German National Academy of Sciences Leopoldina (2021) , and
3729-493: Is deregulated in many cancers as a result of increased activity of PI3K or Akt . Similarly, overexpression of downstream mTOR effectors 4E-BP1 , S6K1 , S6K2 and eIF4E leads to poor cancer prognosis. Also, mutations in TSC proteins that inhibit the activity of mTOR may lead to a condition named tuberous sclerosis complex , which exhibits as benign lesions and increases the risk of renal cell carcinoma . Increasing mTOR activity
3842-419: Is derived from the shikimate pathway . Note that the cyclohexane ring of the starting unit is reduced during the transfer to module 1. The starting unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates, which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each. After each successive condensation , the growing polyketide
3955-414: Is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration . These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates removal of dysfunctional cellular components via autophagy . mTOR is a key initiator of the senescence-associated secretory phenotype (SASP). Interleukin 1 alpha (IL1A)
4068-428: Is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by Cordis , a division of Johnson & Johnson , under
4181-466: Is found on the surface of senescent cells where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB. Translation of mRNA for IL1A is highly dependent upon mTOR activity. mTOR activity increases levels of IL1A, mediated by MAPKAPK2 . mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors. Over-activation of mTOR signaling significantly contributes to
4294-479: Is further modified according to enzymatic domains that are present to reduce and dehydrate it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1). Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS. Then, the NSPS cyclizes the polyketide, giving prerapamycin,
4407-430: Is however needed to develop and create targeted, effective treatment therapies for LM. Due to its immunosuppressant activity, Rapamycin has been assessed as prophylaxis or treatment agent of Graft-versus-host disease (GVHD), a complication of hematopoietic stem cell transplantation . While contrasted results were obtained in clinical trials, pre-clinical studies have shown that Rapamycin can mitigate GVHD by increasing
4520-535: Is indicated for the prophylaxis of organ rejection in adults at low to moderate immunological risk receiving a renal transplant and, as Hyftor, is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis complex. The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even kidney failure ; this can be avoided by using sirolimus instead. It
4633-485: Is mTOR signaling is an example of antagonistic pleiotropy , and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of essential amino acids including leucine and methionine, which are potent activators of mTOR. The administration of leucine into the rat brain has been shown to decrease food intake and body weight via activation of
mTOR - Misplaced Pages Continue
4746-604: Is mediated by the protein complex termed GALTOR. At the heart of GALTOR is galectin-8 , a member of β-galactoside binding superfamily of cytosolic lectins termed galectins , which recognizes lysosomal membrane damage by binding to the exposed glycans on the lumenal side of the delimiting endomembrane. Following membrane damage, galectin-8, which normally associates with mTOR under homeostatic conditions, no longer interacts with mTOR but now instead binds to SLC38A9 , RRAGA / RRAGB , and LAMTOR1 , inhibiting Ragulator 's (LAMTOR1-5 complex) guanine nucleotide exchange function- TOR
4859-421: Is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump . It has linear pharmacokinetics. In studies on N=6 and N=36 subjects, peak concentration was obtained in 1.3 hours +/r- 0.5 hours and the terminal elimination was slow, with a half life around 60 hours +/- 10 hours. Sirolimus was not found to effect the concentration of ciclosporin , which
4972-514: Is not a calcineurin inhibitor , but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on mTOR , and thereby blocks activation of T and B cells . Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin . The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in
5085-461: Is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome , as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use. In 2009, the FDA notified healthcare professionals that
5198-420: Is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity. Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition. Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR
5311-474: Is regulated by rapamycin , insulin, growth factors, phosphatidic acid , certain amino acids and their derivatives (e.g., L -leucine and β-hydroxy β-methylbutyric acid ), mechanical stimuli, and oxidative stress . mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR ( RICTOR ), MLST8 , and mammalian stress-activated protein kinase interacting protein 1 ( mSIN1 ). mTORC2 has been shown to function as an important regulator of
5424-691: Is required for myofibrillar muscle protein synthesis and skeletal muscle hypertrophy in humans in response to both physical exercise and ingestion of certain amino acids or amino acid derivatives. Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during muscle wasting in old age, cancer cachexia , and muscle atrophy from physical inactivity . mTORC2 activation appears to mediate neurite outgrowth in differentiated mouse neuro2a cells . Intermittent mTOR activation in prefrontal neurons by β-hydroxy β-methylbutyrate inhibits age-related cognitive decline associated with dendritic pruning in animals, which
5537-463: Is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q,
5650-415: Is used as an immunosuppressant following organ transplantation. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 (later called Tacrolimus) in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit T-cell receptor (TCR) and IL-2 receptor signaling pathways, respectively. The two natural products were used to discover
5763-589: The Biozentrum University of Basel working with Michael N. Hall and Rao Movva applying yeast genetics to understand the mechanisms of action of immunosuppressive drugs. This work led to the discovery of the cellular growth regulator TOR for which Michael Hall was awarded the Albert Lasker Award for Basic Medical Research in 2017. In 1992, Heitman finished medical school and moved to Duke University to set up his own laboratory in
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#17327720886755876-466: The FK506- and rapamycin-binding proteins , including FKBP12 , and to provide evidence that FKBP12–FK506 and FKBP12–rapamycin might act through gain-of-function mechanisms that target distinct cellular functions. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK506 and rapamycin behave as reciprocal antagonists. These studies implicated FKBP12 as
5989-575: The LC3B / GABARAP conjugation machinery through direct interactions between FIP200/RB1CC1 and ATG16L1 , (ii) ULK1 -ATG13- FIP200/RB1CC1 complex associates with the Beclin 1 - VPS34 - ATG14 via direct interactions between ATG13 's HORMA domain and ATG14 , (iii) ATG16L1 interacts with WIPI2 , which binds to PI3P , the enzymatic product of the class III PI3K Beclin 1-VPS34-ATG14. Thus, mTOR inactivation, initiated through GALTOR upon lysosomal damage, plus
6102-475: The National Academy of Medicine (2024). Heitman's research has largely focused on studies of model and pathogenic fungi to address unsolved problems in biology and medicine. Pioneering research with the model budding yeast Saccharomyces cerevisiae discovered TOR and FKBP12 as the targets of the immunosuppressive and antiproliferative drug rapamycin, now widely used in organ transplantation and cancer chemotherapy. Later studies elucidated key features of how
6215-495: The Ragulator-Rag complex on the lysosome surface where it then becomes active in the presence of sufficient amino acids. mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR ( Raptor ), mammalian lethal with SEC13 protein 8 ( mLST8 ) and the non-core components PRAS40 and DEPTOR . This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1
6328-531: The actin cytoskeleton through its stimulation of F- actin stress fibers, paxillin , RhoA , Rac1 , Cdc42 , and protein kinase C α ( PKCα ). mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival. Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1 and leads to full Akt activation. In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates
6441-477: The cytotoxic effects of chemotherapy drugs, such as doxorubicin or cyclophosphamide . Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2 -positive lymphomas were completely resistant to the therapy; eIF4E -expressing lymphomas are not sensitive to sirolimus. Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that predisposes those afflicted to benign tumor growth in
6554-583: The insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR. Rapamycin ( Sirolimus ) inhibits mTORC1, resulting in the suppression of cellular senescence . This appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Suppression of insulin resistance by sirtuins accounts for at least some of this effect. Impaired sirtuin 3 leads to mitochondrial dysfunction . Rapamycin has
6667-794: The mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors . Sirolimus blocks this pathway. The safety and efficacy of sirolimus treatment of LAM were investigated in clinical trials that compared sirolimus treatment with a placebo group in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers, diarrhea , abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection , headache, dizziness, muscle pain and elevated cholesterol . Serious side effects including hypersensitivity and swelling ( edema ) have been observed in renal transplant patients. While sirolimus
6780-542: The mechanistic target of rapamycin , and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene . mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases . mTOR links with other proteins and serves as a core component of two distinct protein complexes , mTOR complex 1 and mTOR complex 2 , which regulate different cellular processes. In particular, as
6893-472: The 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor. These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in
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#17327720886757006-876: The Department of Molecular Genetics and Microbiology. He was an investigator with the Howard Hughes Medical Institute from 1992 to 2005 and a Burroughs Wellcome Scholar in Molecular Pathogenic Mycology from 1998 to 2005. He became Chair of the Department of Molecular Genetics and Microbiology in 2009. Since 2019, Heitman has been co-director of the Canadian Institute for Advanced Research 's Fungal Kingdom program along with co-director Leah E. Cowen . Heitman's research has been recognized with prestigious awards and funding opportunities, including funding by
7119-573: The European Union in May 2023. Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM). Sirolimus (Fyarro), as protein-bound particles, is indicated for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa). In the EU, sirolimus, as Rapamune,
7232-582: The FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity. Plants express the mechanistic target of rapamycin (mTOR) and have a TOR kinase complex. In plants, only the TORC1 complex is present unlike that of mammalian target of rapamycin which also contains the TORC2 complex. Plant species have TOR proteins in the protein kinase and FKBP-rapamycin binding (FRB) domains that share
7345-849: The Howard Hughes Medical Institute from 1992 to 2005, and an National Institutes of Health MERIT Award from 2011-2021. Several awards have recognized his research accomplishments, including the ASBMB AMGEN Award (2002), the IDSA Squibb Award (2003) (now called the Oswald Avery Award), the Stanley J. Korsmeyer Award (2018) (for key contributions to understanding how microbial pathogens evolve, cause disease, and develop drug resistance and discovery of TOR and FKBP12 as targets of rapamycin),
7458-821: The Rhoda Benham Award (2018), the Edward Novitski Prize (2019) (honoring work on human fungal pathogens and identifying molecular targets of widely used immunosuppressive drugs, a seminal contribution to discovery of TOR, which regulates cell growth in response to nutrients), the American Society for Microbiology 's Award for Basic Research (2019), and the Distinguished Mycologist Award from the Mycological Society of America (2021). Heitman
7571-488: The TOR signaling pathway senses nutrients to control cellular responses. Studies were conducted on the dimorphic transition of Saccharomyces cerevisiae from budding yeast cells to pseudohyphae, elucidating nutrient sensing signaling cascades governing this morphological transition involving GPCR-cAMP-PKA signaling cascades controlling gene expression, and discovering a novel role for the ammonium permease/Rh antigen homolog Mep2 as
7684-690: The TOR1 and TOR2 genes. In 1993, Robert Cafferkey, George Livi, and colleagues, and Jeannette Kunz, Michael N. Hall , and colleagues independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes. Rapamycin arrests fungal activity at the G1 phase of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in T-lymphocytes . Thus, it
7797-535: The ULK1-ATG13 complex, or indirectly, such as components of t he class III PI3K (Beclin 1, ATG14 and VPS34) since they depend on activating phosphorylations by ULK1 when it is not inhibited by mTOR. These autophagy -driving components physically and functionally link up with each other integrating all processes necessary for autophagosomal formation: (i) the ULK1- ATG13 - FIP200/RB1CC1 complex associates with
7910-633: The United States. mTOR , specifically mTORC1, was first shown to be important in aging in 2003, in a study on worms; sirolimus was shown to inhibit and slow aging in worms, yeast, and flies, and then to improve the condition of mouse models of various diseases of aging. Sirolimus was first shown to extend lifespan in wild-type mice in a study published by NIH investigators in 2009; the studies have been replicated in mice of many different genetic backgrounds. A study published in 2020 found late-life sirolimus dosing schedules enhanced mouse lifespan in
8023-523: The brain, heart, kidneys, skin, and other organs. After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and angiomyolipomas in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and everolimus (Novartis's RAD001) to TSC patients off-label. Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in
8136-470: The brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents , prevent organ transplant rejection , treat a rare lung disease called lymphangioleiomyomatosis , and treat perivascular epithelioid cell tumour (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mammalian target of rapamycin (mTOR) kinase inhibitor that reduces
8249-723: The cancer risk in some transplant patients. Sirolimus was shown to inhibit the progression of dermal Kaposi's sarcoma in patients with renal transplants. Other mTOR inhibitors , such as temsirolimus (CCI-779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma . However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs. A combination therapy of doxorubicin and sirolimus has been shown to drive Akt -positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent
8362-737: The control and maintenance of the actin cytoskeleton . The study of TOR (Target Of Rapamycin) originated in the 1960s with an expedition to Easter Island (known by the island inhabitants as Rapa Nui ), with the goal of identifying natural products from plants and soil with possible therapeutic potential. In 1972, Suren Sehgal identified a small molecule, from the soil bacterium Streptomyces hygroscopicus , that he purified and initially reported to possess potent antifungal activity. He named it rapamycin , noting its original source and activity. Early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Rapamycin did not initially receive significant interest from
8475-473: The cortex and hippocampus of animal models of AD compared to controls. Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed. Cognitive impairments characteristic of AD appear to be mediated by
8588-401: The drug's benefits, it also inhibits mTORC2 , which results in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin. Sirolimus treatment may additionally increase the risk of type 2 diabetes. In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus . Lung toxicity
8701-455: The end of the polyketide. The gene rapP , which is embedded between the PKS genes and translationally coupled to rapC , encodes for an additional enzyme , an NPRS responsible for incorporating L-pipecolic acid, chain termination and cyclization of prerapamycin. In addition, genes rapI , rapJ , rapM , rapN , rapO , and rapQ have been identified as coding for tailoring enzymes that modify
8814-433: The execution of lysophagy via autophagic receptors such as p62/ SQSTM1 , which is recruited during lysophagy, or other to be determined functions. Scleroderma , also known as systemic sclerosis , is a chronic systemic autoimmune disease characterised by hardening ( sclero ) of the skin ( derma ) that affects internal organs in its more severe forms. mTOR plays a role in fibrotic diseases and autoimmunity, and blockade of
8927-522: The fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2. Sirolimus
9040-437: The first enzyme-free product. The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin. The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials. Sirolimus seems to lower
9153-686: The first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC. Then, the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin. The core macrocycle , prerapamycin (figure 2),
9266-608: The following phenotypes: Decreased TOR activity has been found to increase life span in S. cerevisiae , C. elegans , and D. melanogaster . The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice. It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity. Some studies have suggested that mTOR signaling may increase during aging, at least in specific tissues like adipose tissue, and rapamycin may act in part by blocking this increase. An alternative theory
9379-526: The galectin-driven processes: Ubiquitination of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above. ATG16L1 has an intrinsic binding affinity for ubiquitin ); whereas ubiquitination by a glycoprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as LAMP1 , LAMP2 , GNS/ N-acetylglucosamine-6-sulfatase , TSPAN6/ tetraspanin-6 , PSAP/ prosaposin , and TMEM192/transmembrane protein 192 may contribute to
9492-1720: The homeodomain proteins Sxi1alpha and Sxi2a, which coordinately control cell type identity and sexual reproduction. Heitman's group has also had a long-standing interest in fungal evolution, describing how cellular processes such as sexual recombination and RNA interference are changed in different fungal lineages, as well as the expansion of the geographic range of the emerging pathogen Cryptococcus gattii . Joseph Heitman has served as co-editor of seven textbooks spanning microbiology, genetics, infectious diseases: The Fungal Kingdom , ASM Press October 2017, editors: Joseph Heitman, Barbara J. Howlett, Pedro W. Crous, Eva H. Stukenbrock, Timothy Yong James, and Neil A.R. Gow.; Sex in Fungi: Molecular Determination and Evolutionary Implications , ASM Press 2007, editors: Joseph Heitman, James W. Kronstad, John W. Taylor, and Lorna A. Casselton.; Cryptococcus: From Human Pathogen to Model Yeast , ASM Press 2011, editors: Joseph Heitman, Thomas R. Kozel, Kyung J. Kwon-Chung , John R. Perfect, and Arturo Casadevall.; Molecular Principles of Fungal Pathogenesis , ASM Press 2006, editors: Joseph Heitman, Scott G. Filler, John E. Edwards Jr., and Aaron P. Mitchell.; Human Fungal Pathogens , Cold Spring Harbor Laboratory Press, 2015, editors: Arturo Casadevall, Aaron P. Mitchell, Judith Berman, Kyung J. Kwon-Chung, John R. Perfect, and Joseph Heitman.; Evolution of Virulence in Eukaryotic Microbes , Wiley Press June 2012, editors: L. David Sibley, Barbara J. Howlett, and Joseph Heitman.; and Yeast as
9605-413: The inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but were not yet well understood according to a 2015 paper. When applied as a topical preparation, researchers showed that rapamycin can regenerate collagen and reverse clinical signs of aging in elderly patients. The concentrations are far lower than those used to treat angiofibromas. Rapamycin has been proposed as
9718-469: The initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor PTEN gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K , an upstream effector of mTOR. Additionally, mTOR activity
9831-462: The laboratories of organic chemist Josef Fried , biochemist Kan Agarwal , and bacteriologist Malcolm Casadaban . In 1984, he began a dual MD–PhD program at Cornell Medical College and Rockefeller University , working on DNA repair in bacteria with Peter Model and Norton Zinder . In 1989, after receiving his PhD from Rockefeller University, Heitman took a leave of absence from medical school to serve as an EMBO -sponsored long-term fellow at
9944-634: The mTOR kinase as its direct target in mammalian tissues. Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2 ) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2) , in studies published in October 1993. The protein, now called mTOR,
10057-428: The mTOR pathway in the hypothalamus . According to the free radical theory of aging , reactive oxygen species cause damage to mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive AMPK , the mTOR pathway is inhibited and ATP-consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome . Hence, the proportion of damaged proteins
10170-529: The mTORC pathway is under investigation as a treatment for scleroderma. mTOR inhibitors, e.g. rapamycin , are already used to prevent transplant rejection . Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS (glycogen synthase) can be increased in skeletal muscle. This discovery represents a potential novel therapeutic approach for glycogen storage disease that involve glycogen accumulation in muscle. Sirolimus Sirolimus , also known as rapamycin and sold under
10283-399: The macrocyclic core to give rapamycin (figure 3). Finally, rapG and rapH have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression. Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which
10396-667: The meaning of the "m" was later changed to "mechanistic". Similarly, with subsequent discoveries the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed by the HUGO Gene Nomenclature Committee (HGNC) to mTOR, which stands for mechanistic target of rapamycin. The discovery of TOR and
10509-406: The natural product rapamycin by Joseph Heitman , Rao Movva, and Michael N. Hall in 1991; by David M. Sabatini , Hediye Erdjument-Bromage, Mary Lui, Paul Tempst, and Solomon H. Snyder in 1994; and by Candace J. Sabers, Mary M. Martin, Gregory J. Brunn, Josie M. Williams, Francis J. Dumont, Gregory Wiederrecht, and Robert T. Abraham in 1995. In 1991, working in yeast, Hall and colleagues identified
10622-405: The pharmaceutical industry until the 1980s, when Wyeth-Ayerst supported Sehgal's efforts to further investigate rapamycin's effect on the immune system. This eventually led to its FDA approval as an immunosuppressant following kidney transplantation. However, prior to its FDA approval, how rapamycin worked remained completely unknown. The discovery of TOR and mTOR stemmed from independent studies of
10735-631: The phosphorylation of PRAS-40, which detaches from and allows for the mTOR hyperactivity when it is phosphorylated; inhibiting PRAS-40 phosphorylation prevents Aβ-induced mTOR hyperactivity. Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD. The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD. p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation. It has also been proposed that mTOR contributes to tau pathology by increasing
10848-614: The plant. However, the TORC1 complex activation stops catabolic processes such as autophagy from occurring. TOR kinase signaling in plants has been found to aid in senescence, flowering, root and leaf growth, embryogenesis, and the meristem activation above the root cap of a plant. mTOR is also found to be highly involved in developing embryo tissue in plants. mTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2. The two complexes localize to different subcellular compartments, thus affecting their activation and function. Upon activation by Rheb, mTORC1 localizes to
10961-572: The presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively. In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway , which in turn activates mTOR. In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles. Chinese hamster ovary cells transfected with
11074-719: The proliferation of regulatory T cells, inhibiting cytotoxic T cells and lowering the differentiation of effector T cells. Rapamycin is used in biology research as an agent for chemically induced dimerization . In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions. A number of veterinary medicine teaching hospitals are participating in
11187-403: The rate of recurrence can be high and surgery can have complications. Sirolimus has shown evidence of being an effective treatment in alleviating symptoms and reducing the size of the malformation by way of altering the mTOR pathway in lymphangiogenesis. Although an off label use of the drug, Sirolimus has been shown to be an effective treatment for both microcystic and macrocystic LM. More research
11300-404: The sensitivity of T cells and B cells to interleukin-2 (IL-2), inhibiting their activity. This compound also has a use in cardiovascular drug-eluting stent technologies to inhibit restenosis . It is produced by the bacterium Streptomyces hygroscopicus and was isolated for the first time in 1972, from samples of Streptomyces hygroscopicus found on Easter Island . The compound
11413-461: The subject of a number of ongoing clinical trials. In May 2015, the FDA approved sirolimus to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This made sirolimus the first drug approved to treat this disease. LAM involves lung tissue infiltration with smooth muscle -like cells with mutations of the tuberous sclerosis complex gene ( TSC2 ). Loss of TSC2 gene function activates
11526-483: The subsequent identification of mTOR opened the door to the molecular and physiological study of what is now called the mTOR pathway and had a catalytic effect on the growth of the field of chemical biology, where small molecules are used as probes of biology. mTOR integrates the input from upstream pathways , including insulin , growth factors (such as IGF-1 and IGF-2 ), and amino acids . mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway
11639-457: The tradename Cypher . However, this kind of stent may also increase the risk of vascular thrombosis. Sirolimus is used to treat vascular malformations. Treatment with sirolimus can decrease pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels. Sirolimus is a relatively new medical therapy for the treatment of vascular malformations in recent years, sirolimus has emerged as
11752-545: The translation of tau and other proteins. Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR. Both protein over- and under-production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it
11865-451: The treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis , nasopharyngitis , acne, upper respiratory tract infection , dizziness, and myalgia . The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant: While sirolimus inhibition of mTORC1 appears to mediate
11978-577: The use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections. Sirolimus may increase an individual's risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma . In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as azathioprine and calcineurin inhibitors , and lower than under placebo . Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have
12091-684: Was approved by the FDA for treating angiofibromas. The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema , hypercholesterolemia , abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia , hypertension , increased creatinine , fever, urinary tract infection , anemia , arthralgia , and thrombocytopenia . The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for
12204-588: Was concluded in 2016 that more research was required before sirolimus could be widely prescribed for this purpose. Two human studies on the effects of sirolimus (rapamycin) on longevity did not show statistically significant benefits. However, due to limitations in the studies, further research is needed to fully assess its potential in humans. Sirolimus has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of
12317-405: Was considered for treatment of LAM, it received orphan drug designation status because LAM is a rare condition. The safety of LAM treatment by sirolimus in people younger than 18 years old has not been tested. The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus
12430-679: Was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1991 in Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German, and the city of Basel was once ringed by a wall punctuated with gates into the city, including the iconic Spalentor . "mTOR" initially meant "mammalian target of rapamycin", but
12543-406: Was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini; FRAP1 was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham, was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein and in homage to the original discovery of the TOR protein in yeast that
12656-460: Was originally named rapamycin after the native name of the island, Rapa Nui. Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR . It was approved by the U.S. Food and Drug Administration (FDA) in 1999. Hyftor (sirolimus gel) was approved for topical treatment of facial angiofibroma in
12769-526: Was shown to drive cell cycle progression and increase cell proliferation mainly due to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting autophagy . Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis . mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism . Akt2 ,
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