Bcl2's flexible loop domain regulates p53 binding and survival.


:p53 not only functions as a transcription factor but also has a direct, apoptogenic role at the mitochondria. We have discovered that DNA damage-induced p53-Bcl2 binding is associated with decreased Bcl2-Bax interaction and increased apoptotic cell death in a mechanism regulated by Bcl2's flexible loop regulatory domain (FLD), since purified p53 protein can disrupt the Bcl2/Bax complex by directly binding to a negative regulatory region of the FLD (amino acids [aa] 32 to 68). Deletion of the negative regulatory region (Delta32-68) abolishes Bcl2-p53 binding and enhances Bcl2's antiapoptotic function. Conversely, removal of a positive regulatory region (aa 69 to 87) of the FLD, which contains the Bcl2 phosphorylation site(s) T69, S70, and S87, enhances Bcl2-p53 binding and significantly abrogates Bcl2's survival activity. The phospho-mimetic T69E/S70E/S87E (EEE) but not the nonphosphorylatable T69A/S70A/S87A (AAA) Bcl2 mutant displays a reduced capacity to bind p53 and potently inhibits p53-induced cytochrome c release from isolated mitochondria. Furthermore, the FLD-only aa32-87 and aa32-68 peptides but not the aa69-87 peptide can directly bind p53 in vitro. p53-induced cytochrome c release occurs through a mechanism involving Bax's integral insertion into the outer mitochondrial membrane. Either DNA damage to cells or expression of p53 selectively targeted to the mitochondria results in Bcl2-p53 binding followed by exposure of Bcl2's BH3 domain in association with inactivation of Bcl2's antiapoptotic function, indicating a conformational change in Bcl2 can occur upon direct ligation of p53. Thus, Bcl2's FLD contains both positive and negative regulatory regions which functionally regulate Bcl2's antiapoptotic activity by affecting Bax or p53 binding.


Mol Cell Biol


Deng X,Gao F,Flagg T,Anderson J,May WS




Has Abstract


2006-06-01 00:00:00














  • A novel Rb- and p300-binding protein inhibits transactivation by MyoD.

    abstract::The retinoblastoma protein (Rb) regulates both the cell cycle and tissue-specific transcription, by modulating the activity of factors that associate with its A-B and C pockets. In skeletal muscle, Rb has been reported to regulate irreversible cell cycle exit and muscle-specific transcription. To identify factors inte...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: MacLellan WR,Xiao G,Abdellatif M,Schneider MD

    更新日期:2000-12-01 00:00:00

  • Association of Rad9 with double-strand breaks through a Mec1-dependent mechanism.

    abstract::Rad9 is required for the activation of DNA damage checkpoint pathways in budding yeast. Rad9 is phosphorylated after DNA damage in a Mec1- and Tel1-dependent manner and subsequently interacts with Rad53. This Rad9-Rad53 interaction has been suggested to trigger the activation and phosphorylation of Rad53. Here we show...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Naiki T,Wakayama T,Nakada D,Matsumoto K,Sugimoto K

    更新日期:2004-04-01 00:00:00

  • 5'-flanking sequence required for regulated expression of a muscle-specific Drosophila melanogaster actin gene.

    abstract::We have functionally tested derivatives of a muscle-specific Drosophila melanogaster actin gene in which 5'-flanking sequences have been deleted or rearranged. From our results we conclude that approximately 1,000 nucleotides of 5'-flanking sequence are required for wild-type levels of mRNA accumulation during flight ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Geyer PK,Fyrberg EA

    更新日期:1986-10-01 00:00:00

  • Deletions of N-terminal sequences of polyoma virus T-antigens reduce but do not abolish transformation of rat fibroblasts.

    abstract::Polyoma virus transforms, upon infection or DNA transfection, nonpermissive Fisher rat fibroblasts. Cloned viral DNA was deleted of sequences around the Bg/I site at nucleotide 86 by Bal31 nuclease treatment and then recloned in Escherichia coli. The extent of deletion for each mutant was then determined by DNA sequen...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Katinka M,Yaniv M

    更新日期:1982-10-01 00:00:00

  • U1A inhibits cleavage at the immunoglobulin M heavy-chain secretory poly(A) site by binding between the two downstream GU-rich regions.

    abstract::The immunoglobulin M heavy-chain locus contains two poly(A) sites which are alternatively expressed during B-cell differentiation. Despite its promoter proximal location, the secretory poly(A) site is not expressed in undifferentiated cells. Crucial to the activation of the secretory poly(A) site during B-cell differe...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Phillips C,Pachikara N,Gunderson SI

    更新日期:2004-07-01 00:00:00

  • Human Cdc34 and Rad6B ubiquitin-conjugating enzymes target repressors of cyclic AMP-induced transcription for proteolysis.

    abstract::Ubiquitin-mediated proteolysis controls diverse physiological processes in eukaryotes. However, few in vivo targets of the mammalian Cdc34 and Rad6 ubiquitin-conjugating enzymes are known. A yeast-based genetic assay to identify proteins that interact with human Cdc34 resulted in three cDNAs encoding bZIP DNA binding ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Pati D,Meistrich ML,Plon SE

    更新日期:1999-07-01 00:00:00

  • Reduction of target gene expression by a modified U1 snRNA.

    abstract::Although the primary function of U1 snRNA is to define the 5' donor site of an intron, it can also block the accumulation of a specific RNA transcript when it binds to a donor sequence within its terminal exon. This work was initiated to investigate if this property of U1 snRNA could be exploited as an effective metho...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Beckley SA,Liu P,Stover ML,Gunderson SI,Lichtler AC,Rowe DW

    更新日期:2001-04-01 00:00:00

  • The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms.

    abstract::Determining the roles of Rel/NF-kappaB transcription factors in mouse skin development with loss-of-function mutants has been limited by redundancy among these proteins and by embryonic lethality associated with the absence of RelA. Using mice lacking RelA and c-rel, which survive throughout embryogenesis on a tumor n...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Gugasyan R,Voss A,Varigos G,Thomas T,Grumont RJ,Kaur P,Grigoriadis G,Gerondakis S

    更新日期:2004-07-01 00:00:00

  • Convergence of protein kinase C and JAK-STAT signaling on transcription factor GATA-4.

    abstract::Angiotensin II (AII), a potent vasoactive hormone, acts on numerous organs via G-protein-coupled receptors and elicits cell-specific responses. At the level of the heart, AII stimulation alters gene transcription and leads to cardiomyocyte hypertrophy. Numerous intracellular signaling pathways are activated in this pr...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Wang J,Paradis P,Aries A,Komati H,Lefebvre C,Wang H,Nemer M

    更新日期:2005-11-01 00:00:00

  • Glycolysis controls plasma membrane glucose sensors to promote glucose signaling in yeasts.

    abstract::Sensing of extracellular glucose is necessary for cells to adapt to glucose variation in their environment. In the respiratory yeast Kluyveromyces lactis, extracellular glucose controls the expression of major glucose permease gene RAG1 through a cascade similar to the Saccharomyces cerevisiae Snf3/Rgt2/Rgt1 glucose s...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Cairey-Remonnay A,Deffaud J,Wésolowski-Louvel M,Lemaire M,Soulard A

    更新日期:2015-02-01 00:00:00

  • The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation.

    abstract::The Werner syndrome protein (WRN) suppresses the loss of telomeres replicated by lagging-strand synthesis by a yet to be defined mechanism. Here, we show that whereas either WRN or the Bloom syndrome helicase (BLM) stimulates DNA polymerase δ progression across telomeric G-rich repeats, only WRN promotes sequential st...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Li B,Reddy S,Comai L

    更新日期:2017-01-19 00:00:00

  • Neuroblastoma cells express c-sis and produce a transforming growth factor antigenically related to the platelet-derived growth factor.

    abstract::Mouse neuroblastoma Neuro-2A cells produce transforming growth factors during exponential growth in a defined hormone-free medium, which, on Bio-Gel columns in 1 M HAc, elute at a molecular size of 15 to 20 kilodaltons (kDa). These neuroblastoma-derived transforming growth factors have strong mitogenic activity, but t...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: van Zoelen EJ,van de Ven WJ,Franssen HJ,van Oostwaard TM,van der Saag PT,Heldin CH,de Laat SW

    更新日期:1985-09-01 00:00:00

  • MEK kinase 1, a substrate for DEVD-directed caspases, is involved in genotoxin-induced apoptosis.

    abstract::MEK kinase 1 (MEKK1) is a 196-kDa protein that, in response to genotoxic agents, was found to undergo phosphorylation-dependent activation. The expression of kinase-inactive MEKK1 inhibited genotoxin-induced apoptosis. Following activation by genotoxins, MEKK1 was cleaved in a caspase-dependent manner into an active 9...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Widmann C,Gerwins P,Johnson NL,Jarpe MB,Johnson GL

    更新日期:1998-04-01 00:00:00

  • Saccharomyces cerevisiae cdc42p GTPase is involved in preventing the recurrence of bud emergence during the cell cycle.

    abstract::The Saccharomyces cerevisiae Cdc42p GTPase interacts with multiple regulators and downstream effectors through an approximately 25-amino-acid effector domain. Four effector domain mutations, Y32K, F37A, D38E, and Y40C, were introduced into Cdc42p and characterized for their effects on these interactions. Each mutant p...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Richman TJ,Johnson DI

    更新日期:2000-11-01 00:00:00

  • Loss of the zymogen granule protein syncollin affects pancreatic protein synthesis and transport but not secretion.

    abstract::Syncollin is a small protein that is abundantly expressed in pancreatic acinar cells and that is tightly associated with the lumenal side of the zymogen granule membrane. To shed light on the hitherto unknown function of syncollin, we have generated syncollin-deficient mice. The mice are viable and show a normal pancr...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Antonin W,Wagner M,Riedel D,Brose N,Jahn R

    更新日期:2002-03-01 00:00:00

  • Mouse germ cell-less as an essential component for nuclear integrity.

    abstract::A mouse homologue of the Drosophila melanogaster germ cell-less (mgcl-1) gene is expressed ubiquitously, and its gene product is localized to the nuclear envelope based on its binding to LAP2 beta (lamina-associated polypeptide 2 beta). To elucidate the role of mgcl-1, we analyzed two mutant mouse lines that lacked mg...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Kimura T,Ito C,Watanabe S,Takahashi T,Ikawa M,Yomogida K,Fujita Y,Ikeuchi M,Asada N,Matsumiya K,Okuyama A,Okabe M,Toshimori K,Nakano T

    更新日期:2003-02-01 00:00:00

  • Myogenic differentiation triggered by antisense acidic fibroblast growth factor RNA.

    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


    authors: Fox JC,Hsu AY,Swain JL

    更新日期:1994-06-01 00:00:00

  • The LIM protein AJUBA recruits protein arginine methyltransferase 5 to mediate SNAIL-dependent transcriptional repression.

    abstract::The SNAIL transcription factor contains C-terminal tandem zinc finger motifs and an N-terminal SNAG repression domain. The members of the SNAIL family have recently emerged as major contributors to the processes of development and metastasis via the regulation of epithelial-mesenchymal transition events during embryon...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Hou Z,Peng H,Ayyanathan K,Yan KP,Langer EM,Longmore GD,Rauscher FJ 3rd

    更新日期:2008-05-01 00:00:00

  • Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series.

    abstract::Glucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (M...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Bowman CE,Zhao L,Hartung T,Wolfgang MJ

    更新日期:2016-07-14 00:00:00

  • In vitro splicing of the terminal intervening sequence of Saccharomyces cerevisiae cytochrome b pre-mRNA.

    abstract::A region of the Saccharomyces cerevisiae mitochondrial cytochrome b gene encompassing the entire terminal intron plus flanking exonic sequences has been cloned in an SP6 vector. A runoff transcript prepared from this construct as well as the native cytochrome b pre-mRNA containing the terminal intervening sequence wer...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Gampel A,Tzagoloff A

    更新日期:1987-07-01 00:00:00

  • Human mRNA cap methyltransferase: alternative nuclear localization signal motifs ensure nuclear localization required for viability.

    abstract::A characteristic feature of gene expression in eukaryotes is the addition of a 5'-terminal 7-methylguanine cap (m7GpppN) to nascent pre-mRNAs in the nucleus catalyzed by capping enzyme and cap methyltransferase. Small interfering RNA (siRNA) knockdown of cap methyltransferase in HeLa cells resulted in apoptosis as mea...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Shafer B,Chu C,Shatkin AJ

    更新日期:2005-04-01 00:00:00

  • Bending DNA can repress a eukaryotic basal promoter and inhibit TFIID binding.

    abstract::Previous studies indicated that repression by eve involves cooperative DNA binding and leads to the formation of a DNA loop which encompasses the DNA sequences normally bound by the RNA polymerase II general transcription factors. To test the general principle of whether bending of a basal promoter sequence can contri...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: TenHarmsel A,Biggin MD

    更新日期:1995-10-01 00:00:00

  • Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity.

    abstract::The GTPase-activating protein (GAP) stimulates the GTPase reaction of p21 by 5 orders of magnitude such that the kcat of the reaction is increased to 19 s-1. Mutations of residues in loop L1 (Gly-12 and Gly-13), in loop L2 (Thr-35 and Asp-38), and in loop L4 (Gln-61 and Glu-63) influence the reaction in different ways...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Gideon P,John J,Frech M,Lautwein A,Clark R,Scheffler JE,Wittinghofer A

    更新日期:1992-05-01 00:00:00

  • The tor pathway regulates gene expression by linking nutrient sensing to histone acetylation.

    abstract::The Tor pathway mediates cell growth in response to nutrient availability, in part by inducing ribosomal protein (RP) gene expression via an unknown mechanism. Expression of RP genes coincides with recruitment of the Esa1 histone acetylase to RP gene promoters. We show that inhibition of Tor with rapamycin releases Es...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Rohde JR,Cardenas ME

    更新日期:2003-01-01 00:00:00

  • A novel intron element operates posttranscriptionally To regulate human N-myc expression.

    abstract::Precisely regulated expression of oncogenes and tumor suppressor genes is essential for normal development, and deregulated expression can lead to cancer. The human N-myc gene normally is expressed in only a subset of fetal epithelial tissues, and its expression is extinguished in all adult tissues except transiently ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Sivak LE,Pont-Kingdon G,Le K,Mayr G,Tai KF,Stevens BT,Carroll WL

    更新日期:1999-01-01 00:00:00

  • Genetic effects of methyl benzimidazole-2-yl-carbamate on Saccharomyces cerevisiae.

    abstract::The genetic effects of the mitotic inhibitor methyl benzimidazole-2-yl-carbamate (MBC) have been studied in Saccharomyces cerevisiae. MBC had little or no effect on the frequency of mutation. In some experiments MBC caused an increase in the frequency of mitotic recombination; however, this effect was small and not re...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Wood JS

    更新日期:1982-09-01 00:00:00

  • Cdh1-anaphase-promoting complex targets Skp2 for destruction in transforming growth factor beta-induced growth inhibition.

    abstract::As a subunit of a ubiquitin ligase, Skp2 is implicated in facilitating cell cycle progression via degradation of various protein targets. We report here that Skp2 is rapidly degraded following cellular stimulation by the cytokine transforming growth factor beta (TGF-beta) and that this degradation stabilizes the cell ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Liu W,Wu G,Li W,Lobur D,Wan Y

    更新日期:2007-04-01 00:00:00

  • Mrc1 marks early-firing origins and coordinates timing and efficiency of initiation in fission yeast.

    abstract::How early- and late-firing origins are selected on eukaryotic chromosomes is largely unknown. Here, we show that Mrc1, a conserved factor required for stabilization of stalled replication forks, selectively binds to the early-firing origins in a manner independent of Cdc45 and Hsk1 kinase in the fission yeast Schizosa...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Hayano M,Kanoh Y,Matsumoto S,Masai H

    更新日期:2011-06-01 00:00:00

  • Telomerase is processive.

    abstract::Telomerase synthesizes tandem repeats of the sequence d(TTGGGG) onto input d(TTGGGG)n primer oligonucleotides (C. W. Greider and E. H. Blackburn, Cell 43:405-413). An intrinsic RNA component of the enzyme provides the template for d(TTGGGG)n repeat synthesis [C. W. Greider and E. H. Blackburn, Nature (London) 337:331-...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Greider CW

    更新日期:1991-09-01 00:00:00

  • Distinct subregions of Swi1 manifest striking differences in prion transmission and SWI/SNF function.

    abstract::We have recently reported that the yeast chromatin-remodeling factor Swi1 can exist as a prion, [SWI(+)], demonstrating a link between prionogenesis and global transcriptional regulation. To shed light on how the Swi1 conformational switch influences Swi1 function and to define the sequence and structural requirements...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Du Z,Crow ET,Kang HS,Li L

    更新日期:2010-10-01 00:00:00