Abstract:
:Signaling downstream of mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) controls specific and distinct aspects of insulin action and nutrient homeostasis in an interconnected and as yet unclear way. Mice lacking the mTORC1 substrate S6 kinase 1 (S6K1) maintain proper glycemic control with a high-fat diet. This phenotype is accompanied by insulin hypersensitivity, Akt- and AMP-activated kinase upregulation, and increased lipolysis in adipose tissue and skeletal muscle. Here, we show that, when S6K1 inactivation is combined with the deletion of the mTORC2 substrate Akt2, glucose homeostasis is compromised due to defects in both insulin action and β-cell function. After a high-fat diet, the S6K1(-/-) Akt2(-/-) double-mutant mice do not become obese, though they are severely hyperglycemic. Our data demonstrate that S6K1 is required for pancreatic β-cell growth and function during adaptation to insulin resistance states. Strikingly, the inactivation of two targets of mTOR and phosphatidylinositol 3-kinase signaling is sufficient to reproduce major hallmarks of type 2 diabetes.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Treins C,Alliouachene S,Hassouna R,Xie Y,Birnbaum MJ,Pende Mdoi
10.1128/MCB.00514-12subject
Has Abstractpub_date
2012-10-01 00:00:00pages
4001-11issue
19eissn
0270-7306issn
1098-5549pii
MCB.00514-12journal_volume
32pub_type
杂志文章abstract::clk-1 encodes a demethoxyubiquinone (DMQ) hydroxylase that is necessary for ubiquinone biosynthesis. When Caenorhabditis elegans clk-1 mutants are grown on bacteria that synthesize ubiquinone (UQ), they are viable but have a pleiotropic phenotype that includes slowed development, behaviors, and aging. However, when gr...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.26.10.3976-3985.2006
更新日期:2006-05-01 00:00:00
abstract::The tyrosinase family comprises three members, tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), and dopachrome tautomerase (Dct). Null mutations and deletions at the Tyr and Tyrp1 loci are known and phenotypically affect coat color due to the absence of enzyme or intracellular mislocalization. At the Dct locus,...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.24.8.3396-3403.2004
更新日期:2004-04-01 00:00:00
abstract::TEL1 is important in Saccharomyces cerevisiae telomere maintenance, and its kinase activity is required. Tel1p associates with telomeres in vivo, is enriched at short telomeres, and enhances the binding of telomerase components to short telomeres. However, it is unclear how the kinase activity and telomere association...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01896-08
更新日期:2009-09-01 00:00:00
abstract::The divergently transcribed DIT1 and DIT2 genes of Saccharomyces cerevisiae, which belong to the mid-late class of sporulation-specific genes, are subject to Ssn6-Tup1-mediated repression in mitotic cells. The Ssn6-Tup1 complex, which is required for repression of diverse sets of coordinately regulated genes, is known...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.15.6772-6788.2005
更新日期:2005-08-01 00:00:00
abstract::Ure2p of Saccharomyces cerevisiae normally functions in blocking utilization of a poor nitrogen source when a good nitrogen source is available. The non-Mendelian genetic element [URE3] is a prion (infectious protein) form of Ure2p, so that overexpression of Ure2p induces the de novo appearance of infectious [URE3]. E...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.19.6.4516
更新日期:1999-06-01 00:00:00
abstract::Histone H3 lysine 9 (H3-K9) methylation has been shown to correlate with transcriptional repression and serve as a specific binding site for heterochromatin protein 1 (HP1). In this study, we investigated the relationship between H3-K9 methylation, transcriptional repression, and HP1 recruitment by comparing the effec...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.7.2525-2538.2005
更新日期:2005-04-01 00:00:00
abstract::There are nearly 50 forkhead (FOX) transcription factors encoded in the human genome and, due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological e...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00881-12
更新日期:2013-01-01 00:00:00
abstract::Acidic fibroblast growth factor (FGF) and related family members regulate differentiation in organisms as diverse as Xenopus laevis and mammals. We utilized a well-characterized model of myogenic development to directly assess the importance of endogenously produced FGF in controlling differentiation. A role for endog...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.14.6.4244
更新日期:1994-06-01 00:00:00
abstract::The human ERCC3 gene, which corrects specifically the nucleotide excision repair defect in human xeroderma pigmentosum group B and cross-complements the repair deficiency in rodent UV-sensitive mutants of group 3, encodes a presumed DNA helicase that is identical to the p89 subunit of the general transcription factor ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.14.6.4126
更新日期:1994-06-01 00:00:00
abstract::A critical event in signaling in immune cells is the interaction of Syk or ZAP-70 protein tyrosine kinases with multisubunit receptors that contain an approximately 18-amino-acid domain called the immunoreceptor tyrosine-based activation motif (ITAM). Tyrosine-phosphorylated Syk from activated cells was in a conformat...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.16.4.1471
更新日期:1996-04-01 00:00:00
abstract::Previous studies have shown that exposure of cells to high levels of replicational stress leads to permanent proliferation arrest that does not require p53. We have examined cellular responses to therapeutically relevant low levels of replicational stress that allow limited proliferation. Chronic exposure to low conce...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01316-06
更新日期:2007-08-01 00:00:00
abstract::In the mouse mammary tumor virus promoter, a tandem of octamer motifs, recognized by ubiquitous and tissue-restricted Oct transcription factors, is located upstream of the TATA box and next to a binding site for the transcription factor nuclear factor I (NF-I). Their function was investigated with mutant long terminal...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.14.2.1191
更新日期:1994-02-01 00:00:00
abstract::Expression of vascular endothelial growth factor (VEGF) increases in cancer cells during hypoxia. Herein, we report that the MDM2 oncoprotein plays a role in hypoxia-mediated VEGF upregulation. In studying the characteristics of MDM2 and VEGF expression in neuroblastoma cells, we found that hypoxia induced significant...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.06085-11
更新日期:2011-12-01 00:00:00
abstract::The Id subfamily of helix-loop-helix (HLH) proteins plays a fundamental role in the regulation of cellular proliferation and differentiation. The major mechanism by which Id proteins are thought to inhibit differentiation is through interaction with other HLH proteins and inhibition of their DNA-binding activity. Howe...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.21.2.524-533.2001
更新日期:2001-01-01 00:00:00
abstract::Mediator is a general coactivator complex connecting transcription activators and RNA polymerase II. Recent work has shown that the nuclear receptor-interacting MED1/TRAP220 subunit of Mediator is required for peroxisome proliferator-activated receptor gamma (PPARgamma)-stimulated adipogenesis of mouse embryonic fibro...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00967-07
更新日期:2008-02-01 00:00:00
abstract::Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4γ was increased in liver-specific Hnf4a-null mi...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00213-18
更新日期:2018-11-28 00:00:00
abstract::Sequence analysis of a mouse testicular alpha-tubulin partial cDNA, pRD alpha TT1, reveals an isotype that differs from both the somatic and the predominant testicular alpha tubulins at approximately 30% of the 212 amino acid residues determined. Although this mouse testicular cDNA retains the highly conserved sequenc...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.8.2.996
更新日期:1988-02-01 00:00:00
abstract::White adipose tissue (WAT) serves as a reversible energy storage depot in the form of lipids in response to nutritional status. Cavin-1, an essential component in the biogenesis of caveolae, is a positive regulator of lipolysis in adipocytes. However, molecular mechanisms of cavin-1 in the modulation of lipolysis rema...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00058-17
更新日期:2017-07-28 00:00:00
abstract::Hypoxia promotes stem cell maintenance and tumor progression, but it remains unclear how it regulates long-term adaptation toward these processes. We reveal a striking downregulation of the hypoxia-inducible histone H3 lysine 9 (H3K9) demethylase JMJD1A as a hallmark of clinical human germ cell-derived tumors, such as...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00099-14
更新日期:2014-10-01 00:00:00
abstract::Mutagenesis studies have demonstrated the requirement for the CD28-responsive element (CD28RE) within the interleukin-2 (IL-2) promoter for transcriptional upregulation by CD28. Here, we demonstrate that CD28 responsiveness is conferred by a composite element containing both the CD28RE and the NF-IL-2B AP-1 sites (RE/...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.17.7.4051
更新日期:1997-07-01 00:00:00
abstract::A key antioxidant pathway, the Keap1-Nrf2 system, is regulated by p62/Sqstm1 via multiple mechanisms, including gene expression, posttranslational modifications (such as ubiquitination and phosphorylation), and autophagic degradation of p62/Sqstm1 and Keap1. Here we demonstrate a novel mode of regulation of the Keap1-...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00642-17
更新日期:2018-03-15 00:00:00
abstract::A gene assigned to human chromosome 1q32-41 encodes a novel protein of 3,113 amino acids containing an internal tandem repeat of 177 amino acids. The protein, which we have named "mitosin," was identified by direct binding to purified retinoblastoma protein in vitro with a region distantly related to the retinoblastom...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.15.9.5017
更新日期:1995-09-01 00:00:00
abstract::A complex pattern of regulation of the cartilage matrix protein gene was revealed by transient expression experiments. A minimal promoter from positions -15 to +64 functioned in chondrocytes and fibroblasts. An enhancer located in the first intron exerted chondrocyte-specific stimulation on the minimal promoter activi...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.10.5.2432
更新日期:1990-05-01 00:00:00
abstract::Both cDNA clones and a genomic DNA clone encoding a 509-amino-acid protein that is 64% similar to chicken pp60c-src were isolated from the simple metazoan Hydra attenuata. We have designated this gene STK, for src-type kinase. Features of the amino acid sequence of the protein encoded by the STK gene suggest that it i...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.9.10.4141
更新日期:1989-10-01 00:00:00
abstract::The message for the zinc finger gene Rex-1 (Zfp-42) is expressed in undifferentiated murine F9 teratocarcinoma cells and embryonic stem cells. Expression of Rex-1 is reduced at the transcriptional level when F9 cells are induced by the addition of retinoic acid (RA) to differentiate. We have isolated genomic DNA for t...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.5.2919
更新日期:1993-05-01 00:00:00
abstract::The tumor suppressor protein ARF inhibits MDM2 to activate and stabilize p53. Recent studies provided evidence for p53-independent tumor suppression functions of ARF. For example, it has been shown that ARF induces proteolysis of certain E2F species, including E2F1. In addition, ARF relocalizes E2F1 from the nucleopla...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.22.24.8398-8408.2002
更新日期:2002-12-01 00:00:00
abstract::The human Ki-ras gene was previously reported to contain two alternative fourth exons which encode two distinct p21 proteins differing only at their carboxy termini. The present study shows that either p21 protein is able on its own to transform NIH 3T3 cells to a tumorigenic state. ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.6.4.1326
更新日期:1986-04-01 00:00:00
abstract::The nuclear enzyme DNA topoisomerase II catalyzes the breakage and resealing of duplex DNA and plays an important role in several genetic processes. It also mediates the DNA cleavage activity and cytotoxicity of clinically important anticancer agents such as etoposide. We have examined the activity of topoisomerase II...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.7.9.3119
更新日期:1987-09-01 00:00:00
abstract::Vimentin is a tissue-specific, developmentally regulated member of the intermediate filament protein family normally expressed in cells of mesenchymal origin. Transcription factors which recognize specific cis-acting elements of the chicken gene include Sp-1 and the 95-kDa silencer protein which binds to a 40-bp silen...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.12.5.2230
更新日期:1992-05-01 00:00:00
abstract::To characterize further the regulatory mechanism modulating the expression of the Saccharomyces cerevisiae ARG3 gene, i.e., the specific repression by arginine and the general amino acid control, we analyzed by deletion the region upstream of that gene, determined the nucleotide sequence of operator-constitutive-like ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.5.11.3139
更新日期:1985-11-01 00:00:00