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Article ; Online: Editorial Expression of Concern: p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.

Flores, Elsa R / Tsai, Kenneth Y / Crowley, Denise / Sengupta, Shomit / Yang, Annie / McKeon, Frank / Jacks, Tyler

2024 Volume 627, Issue 8004, Page(s) E10

Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Expression of Concern
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-024-07223-4
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Discovery of NV-5138, the first selective Brain mTORC1 activator

Shomit Sengupta / Emilie Giaime / Sridhar Narayan / Seung Hahm / Jessica Howell / David O’Neill / George P. Vlasuk / Eddine Saiah

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 10

Abstract: Abstract The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full ... ...

Abstract	Abstract The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Discovery of NV-5138, the first selective Brain mTORC1 activator.

Sengupta, Shomit / Giaime, Emilie / Narayan, Sridhar / Hahm, Seung / Howell, Jessica / O'Neill, David / Vlasuk, George P / Saiah, Eddine

Scientific reports

2019 Volume 9, Issue 1, Page(s) 4107

Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 ... ...

Abstract	The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.
MeSH term(s)	Administration, Oral ; Animals ; Brain/metabolism ; Drug Design ; Drug Discovery ; HEK293 Cells ; Humans ; Leucine/administration & dosage ; Leucine/analogs & derivatives ; Leucine/pharmacokinetics ; Male ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Neurons/metabolism ; Nuclear Proteins/metabolism ; Protein Binding ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Recombinant Proteins/metabolism ; Transaminases/metabolism
Chemical Substances	NV-5138 ; Nuclear Proteins ; RNA, Messenger ; Recombinant Proteins ; SESN2 protein, human ; Transaminases (EC 2.6.1.-) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Leucine (GMW67QNF9C)
Language	English
Publishing date	2019-03-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-40693-5
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Article ; Online: Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters.

Kang, Seong A / O'Neill, David J / Machl, Andreas W / Lumpkin, Casey J / Galda, Stephanie N / Sengupta, Shomit / Mahoney, Sarah J / Howell, Jessica J / Molz, Lisa / Hahm, Seung / Vlasuk, George P / Saiah, Eddine

Cell chemical biology

2019 Volume 26, Issue 9, Page(s) 1203–1213.e13

Abstract: The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic ... ...

Abstract	The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic treatment in certain cell types and in vivo results in the inhibition of both mTORC1 and mTORC2. We have developed a high-throughput cell-based screen for the detection of phosphorylated forms of the mTORC1 (4E-BP1, S6K1) and mTORC2 (Akt) substrates and have identified and characterized a chemical scaffold that demonstrates a profile consistent with the selective inhibition of mTORC1. Stable isotope labeling of amino acids in cell culture-based proteomic target identification revealed that class I glucose transporters were the primary target for these compounds yielding potent inhibition of glucose uptake and, as a result, selective inhibition of mTORC1. The link between the glucose uptake and selective mTORC1 inhibition are discussed in the context of a yet-to-be discovered glucose sensor.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Evaluation, Preclinical/methods ; Glucose/metabolism ; Glucose Transport Proteins, Facilitative/drug effects ; High-Throughput Screening Assays/methods ; Humans ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mechanistic Target of Rapamycin Complex 2/drug effects ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/metabolism ; Phosphorylation ; Proteomics/methods ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Sirolimus/analogs & derivatives ; Sirolimus/metabolism ; Sirolimus/pharmacology ; Transcription Factors/metabolism
Chemical Substances	Glucose Transport Proteins, Facilitative ; Multiprotein Complexes ; Transcription Factors ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Glucose (IY9XDZ35W2) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2019-06-20
Publishing country	United States
Document type	Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2019.05.009
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress.

Sengupta, Shomit / Peterson, Timothy R / Sabatini, David M

Molecular cell

2010 Volume 40, Issue 2, Page(s) 310–322

Abstract: The large serine/threonine protein kinase mTOR regulates cellular and organismal homeostasis by coordinating anabolic and catabolic processes with nutrient, energy, and oxygen availability and growth factor signaling. Cells and organisms experience a ... ...

Abstract	The large serine/threonine protein kinase mTOR regulates cellular and organismal homeostasis by coordinating anabolic and catabolic processes with nutrient, energy, and oxygen availability and growth factor signaling. Cells and organisms experience a wide variety of insults that perturb the homeostatic systems governed by mTOR and therefore require appropriate stress responses to allow cells to continue to function. Stress can manifest from an excess or lack of upstream signals or as a result of genetic perturbations in upstream effectors of the pathway. mTOR nucleates two large protein complexes that are important nodes in the pathways that help buffer cells from stresses, and are implicated in the progression of stress-associated phenotypes and diseases, such as aging, tumorigenesis, and diabetes. This review focuses on the key components of the mTOR complex 1 pathway and on how various stresses impinge upon them.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Food ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Models, Biological ; Multiprotein Complexes ; Phosphatidylinositol 3-Kinases/metabolism ; Proteins ; Signal Transduction/physiology ; Stress, Physiological/physiology ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Intercellular Signaling Peptides and Proteins ; Multiprotein Complexes ; Proteins ; Transcription Factors ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2010-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2010.09.026
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Article ; Online: mTORC1 controls fasting-induced ketogenesis and its modulation by ageing.

Sengupta, Shomit / Peterson, Timothy R / Laplante, Mathieu / Oh, Stephanie / Sabatini, David M

Nature

2010 Volume 468, Issue 7327, Page(s) 1100–1104

Abstract: The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the ... ...

Abstract	The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1 (tuberous sclerosis 1), an mTORC1 inhibitor, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1) an essential mTORC1 component, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARα (peroxisome proliferator activated receptor α), the master transcriptional activator of ketogenic genes, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARα, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARα activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARα function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.
MeSH term(s)	Aging ; Animals ; Cell Line ; Fasting/metabolism ; Gene Expression Regulation ; Humans ; Ketone Bodies/biosynthesis ; Ketone Bodies/metabolism ; Liver/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Multiprotein Complexes ; Nuclear Receptor Co-Repressor 1/metabolism ; PPAR alpha/antagonists & inhibitors ; PPAR alpha/metabolism ; Proteins/genetics ; Proteins/metabolism ; TOR Serine-Threonine Kinases
Chemical Substances	Ketone Bodies ; Multiprotein Complexes ; Ncor1 protein, mouse ; Nuclear Receptor Co-Repressor 1 ; PPAR alpha ; Proteins ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2010-12-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature09584
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: p63 and p73 transcriptionally regulate genes involved in DNA repair.

Lin, Yu-Li / Sengupta, Shomit / Gurdziel, Katherine / Bell, George W / Jacks, Tyler / Flores, Elsa R

publication RETRACTED

PLoS genetics

2009 Volume 5, Issue 10, Page(s) e1000680

Abstract: The p53 family activates many of the same genes in response to DNA damage. Because p63 and p73 have structural differences from p53 and play distinct biological functions in development and metastasis, it is likely that they activate a unique ... ...

Abstract	The p53 family activates many of the same genes in response to DNA damage. Because p63 and p73 have structural differences from p53 and play distinct biological functions in development and metastasis, it is likely that they activate a unique transcriptional network. Therefore, we performed a genome-wide analysis using cells lacking the p53 family members after treatment with DNA damage. We identified over 100 genes involved in multiple pathways that were uniquely regulated by p63 or p73, and not p53. Further validation indicated that BRCA2, Rad51, and mre11 are direct transcriptional targets of p63 and p73. Additionally, cells deficient for p63 and p73 are impaired in DNA repair and p63+/-;p73+/- mice develop mammary tumors suggesting a novel mechanism whereby p63 and p73 suppress tumorigenesis.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Animals ; BRCA2 Protein/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Survival/genetics ; Cells, Cultured ; Chromatin Immunoprecipitation ; Cluster Analysis ; DNA Repair ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Immunohistochemistry ; MRE11 Homologue Protein ; Mice ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Promoter Regions, Genetic ; Rad51 Recombinase/metabolism ; Radiation, Ionizing ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcriptional Activation/genetics ; Tumor Protein p73 ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
Chemical Substances	BRCA2 Protein ; BRCA2 protein, mouse ; DNA-Binding Proteins ; Mre11a protein, mouse ; Nuclear Proteins ; Phosphoproteins ; Trans-Activators ; Trp63 protein, mouse ; Trp73 protein, mouse ; Tumor Protein p73 ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins ; Rad51 Recombinase (EC 2.7.7.-) ; Rad51 protein, mouse (EC 2.7.7.-) ; MRE11 Homologue Protein (EC 3.1.-) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2009-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Retracted Publication
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1000680
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Article: Uropathogenic Escherichia coli induces extrinsic and intrinsic cascades to initiate urothelial apoptosis.

Klumpp, David J / Rycyk, Matthew T / Chen, Michael C / Thumbikat, Praveen / Sengupta, Shomit / Schaeffer, Anthony J

Infection and immunity

2006 Volume 74, Issue 9, Page(s) 5106–5113

Abstract: A murine model of urinary tract infection identified urothelial apoptosis as a key event in the pathogenesis mediated by uropathogenic Escherichia coli (UPEC), yet the mechanism of this important host response is not well characterized. We employed a ... ...

Abstract	A murine model of urinary tract infection identified urothelial apoptosis as a key event in the pathogenesis mediated by uropathogenic Escherichia coli (UPEC), yet the mechanism of this important host response is not well characterized. We employed a culture model of UPEC-urothelium interactions to examine the biochemical events associated with urothelial apoptosis induced by the UPEC strain NU14. NU14 induced DNA cleavage within 5 h that was inhibited by the broad caspase inhibitor ZVAD, and urothelial caspase 3 activity was induced within 3 h of exposure to type 1 piliated NU14 and was dependent upon interactions mediated by the type 1 pilus adhesin FimH. Flow cytometry experiments using chloromethyl-X-rosamine and Indo-1 revealed FimH-dependent mitochondrial membrane depolarization and elevated [Ca(2+)](in), respectively, indicating activation of the intrinsic apoptotic pathway. Consistent with this possibility, overexpression of Bcl(XL) inhibited NU14 activation of caspase 3. Immunoblotting, caspase inhibitors, and caspase activity assays implicated both caspase 2 and caspase 8 in apoptosis, suggesting the involvement of the intrinsic and extrinsic apoptotic cascades. To reconcile the apparent activation of both extrinsic and intrinsic pathways, we examined Bid-green fluorescent protein localization and observed translocation from the cytosol to mitochondria in response to either NU14 or purified FimH. These data suggest that FimH acts as a tethered toxin of UPEC that activates caspase-dependent urothelial apoptosis via direct induction of the extrinsic pathway and that the intrinsic pathway is activated indirectly as a result of coupling by caspase 8-mediated Bid cleavage.
MeSH term(s)	Adhesins, Escherichia coli/metabolism ; Apoptosis ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Bacterial Adhesion ; Calcium/metabolism ; Caspase 2 ; Caspase 8 ; Caspase Inhibitors ; Caspases/metabolism ; Cells, Cultured ; Cysteine Proteinase Inhibitors/pharmacology ; Escherichia coli/metabolism ; Escherichia coli/pathogenicity ; Escherichia coli Infections/microbiology ; Escherichia coli Infections/pathology ; Fimbriae Proteins/metabolism ; Flow Cytometry ; Humans ; Mitochondrial Membranes/metabolism ; Models, Biological ; Protein Transport ; Urinary Tract Infections/microbiology ; Urinary Tract Infections/pathology ; Urothelium/microbiology ; Urothelium/pathology ; bcl-X Protein/metabolism
Chemical Substances	Adhesins, Escherichia coli ; BCL2L1 protein, human ; BH3 Interacting Domain Death Agonist Protein ; Caspase Inhibitors ; Cysteine Proteinase Inhibitors ; bcl-X Protein ; fimH protein, E coli ; Fimbriae Proteins (147680-16-8) ; CASP8 protein, human (EC 3.4.22.-) ; Caspase 2 (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2006-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.00376-06
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Article ; Online: mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.

Peterson, Timothy R / Sengupta, Shomit S / Harris, Thurl E / Carmack, Anne E / Kang, Seong A / Balderas, Eric / Guertin, David A / Madden, Katherine L / Carpenter, Anne E / Finck, Brian N / Sabatini, David M

Cell

2011 Volume 146, Issue 3, Page(s) 408–420

Abstract: The nutrient- and growth factor-responsive kinase mTOR complex 1 (mTORC1) regulates many processes that control growth, including protein synthesis, autophagy, and lipogenesis. Through unknown mechanisms, mTORC1 promotes the function of SREBP, a master ... ...

Abstract	The nutrient- and growth factor-responsive kinase mTOR complex 1 (mTORC1) regulates many processes that control growth, including protein synthesis, autophagy, and lipogenesis. Through unknown mechanisms, mTORC1 promotes the function of SREBP, a master regulator of lipo- and sterolgenic gene transcription. Here, we demonstrate that mTORC1 regulates SREBP by controlling the nuclear entry of lipin 1, a phosphatidic acid phosphatase. Dephosphorylated, nuclear, catalytically active lipin 1 promotes nuclear remodeling and mediates the effects of mTORC1 on SREBP target gene, SREBP promoter activity, and nuclear SREBP protein abundance. Inhibition of mTORC1 in the liver significantly impairs SREBP function and makes mice resistant, in a lipin 1-dependent fashion, to the hepatic steatosis and hypercholesterolemia induced by a high-fat and -cholesterol diet. These findings establish lipin 1 as a key component of the mTORC1-SREBP pathway.
MeSH term(s)	Animals ; Humans ; Lipid Metabolism ; Male ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Multiprotein Complexes ; Nuclear Proteins/metabolism ; Phosphatidate Phosphatase ; Proteins/metabolism ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1/metabolism ; Sterol Regulatory Element Binding Protein 2/metabolism ; TOR Serine-Threonine Kinases
Chemical Substances	Multiprotein Complexes ; Nuclear Proteins ; Proteins ; Sterol Regulatory Element Binding Protein 1 ; Sterol Regulatory Element Binding Protein 2 ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Lpin1 protein, mouse (EC 3.1.3.4) ; Phosphatidate Phosphatase (EC 3.1.3.4)
Language	English
Publishing date	2011-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2011.06.034
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Article: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.

Sarbassov, Dos D / Ali, Siraj M / Sengupta, Shomit / Sheen, Joon-Ho / Hsu, Peggy P / Bagley, Alex F / Markhard, Andrew L / Sabatini, David M

Molecular cell

2006 Volume 22, Issue 2, Page(s) 159–168

Abstract: The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a ... ...

Abstract	The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types.
MeSH term(s)	Animals ; Antibiotics, Antineoplastic/pharmacology ; Apoptosis/drug effects ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects ; HT29 Cells ; HeLa Cells ; Humans ; Immunoblotting ; Immunohistochemistry ; Jurkat Cells ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Phosphorylation/drug effects ; Precipitin Tests ; Proto-Oncogene Proteins c-akt/analysis ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/genetics ; Retroviridae/genetics ; Signal Transduction/drug effects ; Sirolimus/pharmacology ; Time Factors ; Trans-Activators/antagonists & inhibitors ; Transcription Factors ; Transplantation, Heterologous
Chemical Substances	Antibiotics, Antineoplastic ; Crtc2 protein, mouse ; Trans-Activators ; Transcription Factors ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2006-04-06
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2006.03.029
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