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














  • Myeloma mutant with a novel 3' flanking region: loss of normal sequence and insertion of repetitive elements leads to decreased transcription but normal processing of the alpha heavy-chain gene products.

    abstract::We isolated and characterized LP1.2, a mouse myeloma mutant with a deletion of at least 4 kilobases (kb) immediately 3' of the alpha gene and introduction of at least 5 kb of novel (nonimmunoglobulin) sequence in its place. A 6.2-kb genomic EcoRI fragment from the mutated allele was cloned, and a subfragment was seque...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Gregor PD,Morrison SL

    更新日期:1986-06-01 00:00:00

  • DOT4 links silencing and cell growth in Saccharomyces cerevisiae.

    abstract::Transcriptional silencing in Saccharomyces cerevisiae occurs at specific loci and is mediated by a multiprotein complex that includes Rap1p and the Sir proteins. We studied the function of a recently identified gene, DOT4, that disrupts silencing when overexpressed. DOT4 encodes an ubiquitin processing protease (hydro...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Kahana A,Gottschling DE

    更新日期:1999-10-01 00:00:00

  • Microcell-mediated cotransfer of genes specifying methotrexate resistance, emetine sensitivity, and chromate sensitivity with Chinese hamster chromosome 2.

    abstract::Many selectable mutants of somatic Chinese hamster cells have been described, but very few of the mutations have been mapped to specific chromosomes. We have utilized the microcell-mediated gene transfer technique to establish the location of three selectable genetic markers on chromosome 2 of Chinese hamster. Microce...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Worton R,Duff C,Flintoff W

    更新日期:1981-04-01 00:00:00

  • Mammalian Llgl2 is necessary for proper branching morphogenesis during placental development.

    abstract::Cell polarity plays a critical role in the development of all metazoans; however, the mechanisms of cell polarity and the specific role of cell polarity pathways in mammalian organisms are still poorly understood. Lethal giant larvae (Lgl) is an apical-basal polarity gene identified in Drosophila, where it functions a...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Sripathy S,Lee M,Vasioukhin V

    更新日期:2011-07-01 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

  • Repression of CDK1 and other genes with CDE and CHR promoter elements during DNA damage-induced G(2)/M arrest in human cells.

    abstract::Entry into mitosis is controlled by the cyclin-dependent kinase CDK1 and can be delayed in response to DNA damage. In some systems, such G(2)/M arrest has been shown to reflect the stabilization of inhibitory phosphorylation sites on CDK1. In human cells, full G(2) arrest appears to involve additional mechanisms. We d...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Badie C,Itzhaki JE,Sullivan MJ,Carpenter AJ,Porter AC

    更新日期:2000-04-01 00:00:00

  • Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells.

    abstract::A recent analysis of gene expression in renal cell carcinoma cells led to the identification of mRNAs whose translation was dependent on the presence of the von Hippel-Lindau (VHL) tumor suppressor gene product, pVHL. Here, we investigate the finding that pVHL-expressing RCC cells (VHL(+)) exhibited elevated levels of...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Galbán S,Martindale JL,Mazan-Mamczarz K,López de Silanes I,Fan J,Wang W,Decker J,Gorospe M

    更新日期:2003-10-01 00:00:00

  • p300/CREB binding protein-related protein p270 is a component of mammalian SWI/SNF complexes.

    abstract::p300 and the closely related CREB binding protein (CBP) are transcriptional adaptors that are present in intracellular complexes with TATA binding protein (TBP) and bind to upstream activators including p53 and nuclear hormone receptors. They have intrinsic and associated histone acetyltransferase activity, suggesting...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Dallas PB,Cheney IW,Liao DW,Bowrin V,Byam W,Pacchione S,Kobayashi R,Yaciuk P,Moran E

    更新日期:1998-06-01 00:00:00

  • The alternatively spliced exon of the platelet-derived growth factor A chain encodes a nuclear targeting signal.

    abstract::We have previously shown that the SIS/platelet-derived growth factor B chain contains a nuclear targeting signal near its C terminus. Here we show that the platelet-derived growth factor A chain also contains a nuclear targeting signal encoded by an exon which is subject to alternative splicing. This sequence is capab...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Maher DW,Lee BA,Donoghue DJ

    更新日期:1989-05-01 00:00:00

  • Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts.

    abstract::By assessing the contribution of deregulated E2F activity to erythroid defects in Rb null mice, we have identified E2f-2 as being upregulated in end-stage red cells, where we show it is the major pRb-associated E2f and the predominant E2f detected at key target gene promoters. Consistent with its expression pattern, E...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Dirlam A,Spike BT,Macleod KF

    更新日期:2007-12-01 00:00:00

  • Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase.

    abstract::Substitution of phenylalanine for tyrosine at codon 809 (Y809F) of the human colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) impairs ligand-stimulated tyrosine kinase activity, prevents induction of c-MYC and cyclin D1 genes, and blocks CSF-1-dependent progression through the G1 phase of the cell cycle. We devis...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Davis JN,Rock CO,Cheng M,Watson JB,Ashmun RA,Kirk H,Kay RJ,Roussel MF

    更新日期:1997-12-01 00:00:00

  • Cln3-associated kinase activity in Saccharomyces cerevisiae is regulated by the mating factor pathway.

    abstract::The Saccharomyces cerevisiae cell cycle is arrested in G1 phase by the mating factor pathway. Genetic evidence has suggested that the G1 cyclins Cln1, Cln2, and Cln3 are targets of this pathway whose inhibition results in G1 arrest. Inhibition of Cln1- and Cln2-associated kinase activity by the mating factor pathway a...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Jeoung DI,Oehlen LJ,Cross FR

    更新日期:1998-01-01 00:00:00

  • Immunologically distinct p53 molecules generated by alternative splicing.

    abstract::Transfection of a functional cloned p53 gene into an L12 p53 nonproducer cell line efficiently reconstituted p53 expression. The p53 protein synthesized in these clones was indistinguishable from that occurring naturally in tumor cells. When a p53 cDNA clone was used instead, we observed that the L12-derived clones ex...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Arai N,Nomura D,Yokota K,Wolf D,Brill E,Shohat O,Rotter V

    更新日期:1986-09-01 00:00:00

  • Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis.

    abstract::Mitoferrin 1 (Mfrn1; Slc25a37) and mitoferrin 2 (Mfrn2; Slc25a28) function as essential mitochondrial iron importers for heme and Fe/S cluster biogenesis. A genetic deficiency of Mfrn1 results in a profound hypochromic anemia in vertebrate species. To map the cis-regulatory modules (CRMs) that control expression of th...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Amigo JD,Yu M,Troadec MB,Gwynn B,Cooney JD,Lambert AJ,Chi NC,Weiss MJ,Peters LL,Kaplan J,Cantor AB,Paw BH

    更新日期:2011-04-01 00:00:00

  • Recombinational instability of a chimeric plasmid in Saccharomyces cerevisiae.

    abstract::Wild-type strains of Saccharomyces cerevisiae exhibit mitotic recombination between the chimeric plasmid TLC-1 and the endogenous 2mu circle that involves sequence homologies between the two plasmids that are not acted on by the 2mu circle site-specific recombination system. This generalized recombination can be detec...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Whiteway MS,Ahmed A

    更新日期:1984-01-01 00:00:00

  • Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription.

    abstract::Smad6 and Smad7 are inhibitory Smads induced by transforming growth factor beta-Smad signal transduction pathways in a negative-feedback mechanism. Previously it has been thought that inhibitory Smads bind to the type I receptor and block the phosphorylation of receptor-activated Smads, thereby inhibiting the initiati...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Lin X,Liang YY,Sun B,Liang M,Shi Y,Brunicardi FC,Shi Y,Feng XH

    更新日期:2003-12-01 00:00:00

  • NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration.

    abstract::Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migra...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Hedrick E,Lee SO,Doddapaneni R,Singh M,Safe S

    更新日期:2016-04-15 00:00:00

  • Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo.

    abstract::The E2F1, -2, and -3 transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor that drive expression of proliferation-associated genes. Here we use mutant mouse strains to investigate E2F3's role in vivo. We show that E2F3 is essential for embryonic viability in the pure 129...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Cloud JE,Rogers C,Reza TL,Ziebold U,Stone JR,Picard MH,Caron AM,Bronson RT,Lees JA

    更新日期:2002-04-01 00:00:00

  • Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1 mRNA level and impairs cell growth.

    abstract::The stability of mRNA influences the abundance of cellular transcripts and proteins. Deadenylases play critical roles in mRNA turnover and thus are important for the regulation of various biological events. Here, we report the identification and characterization of CCR4b/CNOT6L, which is homologous to yeast CCR4 mRNA ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Morita M,Suzuki T,Nakamura T,Yokoyama K,Miyasaka T,Yamamoto T

    更新日期:2007-07-01 00:00:00

  • Control of types I and II collagen and fibronectin gene expression in chondrocytes delineated by viral transformation.

    abstract::We have analyzed the effects of transformation by Rous sarcoma virus on expression of types I and II collagen and fibronectin genes in vertebral chondrocytes and compared them with expression of these genes in skin fibroblasts. Transformed chondrocytes display a dramatically decreased amount of type II collagen RNA, w...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Allebach ES,Boettiger D,Pacifici M,Adams SL

    更新日期:1985-05-01 00:00:00

  • Identification of the crossover site during FLP-mediated recombination in the Saccharomyces cerevisiae plasmid 2 microns circle.

    abstract::The FLP protein of the Saccharomyces cerevisiae plasmid 2 microns circle catalyzes site-specific recombination between two repeated segments present on the plasmid. In this paper we present results of experiments we performed to define more precisely the features of the FLP recognition target site, which we propose to...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: McLeod M,Craft S,Broach JR

    更新日期:1986-10-01 00:00:00

  • Interaction of the FLP recombinase of the Saccharomyces cerevisiae 2 micron plasmid with mutated target sequences.

    abstract::The 2 micron plasmid of Saccharomyces cerevisiae codes for a site-specific recombinase, the FLP protein, that catalyzes efficient recombination across two 599-base-pair (bp) inverted repeats of the plasmid DNA both in vivo and in vitro. We analyzed the interaction of the purified FLP protein with the target sequences ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Andrews BJ,McLeod M,Broach J,Sadowski PD

    更新日期:1986-07-01 00:00:00

  • Asp1 Bifunctional Activity Modulates Spindle Function via Controlling Cellular Inositol Pyrophosphate Levels in Schizosaccharomyces pombe.

    abstract::The generation of two daughter cells with the same genetic information requires error-free chromosome segregation during mitosis. Chromosome transmission fidelity is dependent on spindle structure/function, which requires Asp1 in the fission yeast Schizosaccharomyces pombe Asp1 belongs to the diphosphoinositol pentaki...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Pascual-Ortiz M,Saiardi A,Walla E,Jakopec V,Künzel NA,Span I,Vangala A,Fleig U

    更新日期:2018-04-16 00:00:00

  • HOXA9 participates in the transcriptional activation of E-selectin in endothelial cells.

    abstract::The homeobox gene HOXA9 has recently been shown to be an important regulator of endothelial cell (EC) differentiation and activation in addition to its role in embryonic development and hematopoiesis. In this report, we have determined that the EC-leukocyte adhesion molecule E-selectin is a key target for HOXA9. The d...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Bandyopadhyay S,Ashraf MZ,Daher P,Howe PH,DiCorleto PE

    更新日期:2007-06-01 00:00:00

  • Altered states of telomere deprotection and the two-stage mechanism of replicative aging.

    abstract::The molecular distinctions between mortality stages 1 (M1; senescence) and 2 (M2; crisis) of human replicative aging are ill defined. We demonstrate a qualitative difference between telomeric end associations at M1 and the end fusions that produce dicentric chromosomes and breakage-fusion cycles. Knockdown of ligase I...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Zou Y,Misri S,Shay JW,Pandita TK,Wright WE

    更新日期:2009-05-01 00:00:00

  • Enhancer-dependent transcription of the epsilon-globin promoter requires promoter-bound GATA-1 and enhancer-bound AP-1/NF-E2.

    abstract::We analyzed epsilon-globin transcription in erythroid cells and in erythroid extracts to determine the requirements for enhancer-dependent expression of this gene. Mutations that abolished GATA-1 binding at a single position in the promoter prevented interaction with enhancers, whereas elimination of a second more dis...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Gong Q,Dean A

    更新日期:1993-02-01 00:00:00

  • The cytomegalovirus enhancer: a pan-active control element in transgenic mice.

    abstract::In an effort to identify widely active positive regulatory elements, we have examined the action of the cytomegalovirus enhancer-promoter in transgenic mice. These elements activated expression in 24 of 28 tissues tested. The greatest expression was observed in the heart, kidney, brain, and testis. Maximum expression ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Schmidt EV,Christoph G,Zeller R,Leder P

    更新日期:1990-08-01 00:00:00

  • Nuclear factor I X deficiency causes brain malformation and severe skeletal defects.

    abstract::The transcription factor family of nuclear factor I (NFI) proteins is encoded by four closely related genes: Nfia, Nfib, Nfic, and Nfix. A potential role for NFI proteins in regulating developmental processes has been implicated by their specific expression pattern during embryonic development and by analysis of NFI-d...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Driller K,Pagenstecher A,Uhl M,Omran H,Berlis A,Gründer A,Sippel AE

    更新日期:2007-05-01 00:00:00

  • Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb.

    abstract::The pocket protein family of tumor suppressors, and Rb specifically, have been implicated as controlling terminal differentiation in many tissues, including the heart. To establish the biological functions of Rb in the heart and overcome the early lethality caused by germ line deletion of Rb, we used a Cre/loxP system...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: MacLellan WR,Garcia A,Oh H,Frenkel P,Jordan MC,Roos KP,Schneider MD

    更新日期:2005-03-01 00:00:00

  • Polyamines regulate the stability of JunD mRNA by modulating the competitive binding of its 3' untranslated region to HuR and AUF1.

    abstract::Polyamines critically regulate all mammalian cell growth and proliferation by mechanisms such as the repression of growth-inhibitory proteins, including JunD. Decreasing the levels of cellular polyamines stabilizes JunD mRNA without affecting its transcription, but the exact mechanism whereby polyamines regulate JunD ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Zou T,Rao JN,Liu L,Xiao L,Yu TX,Jiang P,Gorospe M,Wang JY

    更新日期:2010-11-01 00:00:00