Age-related macular degeneration-associated silent polymorphisms in HtrA1 impair its ability to antagonize insulin-like growth factor 1.


:Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD.


Mol Cell Biol


Jacobo SM,Deangelis MM,Kim IK,Kazlauskas A




Has Abstract


2013-05-01 00:00:00














  • Characterization of factors that direct transcription of rat ribosomal DNA.

    abstract::The protein components that direct and activate accurate transcription by rat RNA polymerase I were studied in extracts of Novikoff hepatoma ascites cells. A minimum of at least two components, besides RNA polymerase I, that are necessary for efficient utilization of templates were identified. The first factor, rat SL...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Smith SD,Oriahi E,Lowe D,Yang-Yen HF,O'Mahony D,Rose K,Chen K,Rothblum LI

    更新日期:1990-06-01 00:00:00

  • Zebra fish myc family and max genes: differential expression and oncogenic activity throughout vertebrate evolution.

    abstract::To gain insight into the role of Myc family oncoproteins and their associated protein Max in vertebrate growth and development, we sought to identify homologs in the zebra fish (Brachydanio rerio). A combination of a polymerase chain reaction-based cloning strategy and low-stringency hybridization screening allowed fo...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Schreiber-Agus N,Horner J,Torres R,Chiu FC,DePinho RA

    更新日期:1993-05-01 00:00:00

  • Activation of yeast polymerase II transcription by herpesvirus VP16 and GAL4 derivatives in vitro.

    abstract::Fusion proteins known to activate transcription in vivo were tested for the ability to stimulate transcription in vitro in a recently developed Saccharomyces cerevisiae RNA polymerase II transcription system. One fusion protein, whose activation domain was derived from the herpesvirus transcriptional activator VP16, g...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Chasman DI,Leatherwood J,Carey M,Ptashne M,Kornberg RD

    更新日期:1989-11-01 00:00:00

  • Transcriptional activity of neural retina leucine zipper (Nrl) is regulated by c-Jun N-terminal kinase and Tip60 during retina development.

    abstract::Neural retina leucine zipper (Nrl), a key basic motif leucine zipper (bZIP) transcription factor, modulates rod photoreceptor differentiation by activating rod-specific target genes. In searching for factors that might couple with Nrl to modulate its transcriptional activity through posttranslational modification, we ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Kim JW,Jang SM,Kim CH,An JH,Choi KH

    更新日期:2012-05-01 00:00:00

  • Nuclear function of Smad7 promotes myogenesis.

    abstract::In the "canonical" view of transforming growth factor beta (TGF-beta) signaling, Smad7 plays an inhibitory role. While Smad7 represses Smad3 activation by TGF-beta, it does not reverse the inhibitory effect of TGF-beta on myogenesis, suggesting a different function in myogenic cells. We previously reported a promyogen...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Miyake T,Alli NS,McDermott JC

    更新日期:2010-02-01 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

  • Modulation of transcriptional activation of the proliferating cell nuclear antigen promoter by the adenovirus E1A 243-residue oncoprotein depends on proximal activators.

    abstract::Previous analyses defined a proliferating cell nuclear antigen (PCNA) E1A-responsive element (PERE) in the PCNA promoter that is essential for transactivation by the 243-residue product of the adenovirus type 2 E1A 12S mRNA (E1A 243R). In this report, we show that the PERE activates a heterologous basal promoter and c...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Morris GF,Labrie C,Mathews MB

    更新日期:1994-01-01 00:00:00

  • Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell-cell dissociation during cell scattering.

    abstract::We have previously proposed that IQGAP1, an effector of Rac1 and Cdc42, negatively regulates cadherin-mediated cell-cell adhesion by interacting with beta-catenin and by causing the dissociation of alpha-catenin from cadherin-beta-catenin-alpha-catenin complexes and that activated Rac1 and Cdc42 positively regulate ca...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Fukata M,Nakagawa M,Itoh N,Kawajiri A,Yamaga M,Kuroda S,Kaibuchi K

    更新日期:2001-03-01 00:00:00

  • Identification of a region within the Na,K-ATPase alpha subunit that contributes to differential ouabain sensitivity.

    abstract::To analyze determinants within the Na,K-ATPase alpha subunit that contribute to differential ouabain sensitivity, we constructed and expressed a panel of chimeric cDNA molecules between ouabain-resistant and ouabain-sensitive alpha subunit cDNAs. When introduced into ouabain-sensitive monkey CV-1 cells, ouabain-resist...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Emanuel JR,Graw S,Housman D,Levenson R

    更新日期:1989-09-01 00:00:00

  • Saccharomyces cerevisiae expresses three functionally distinct homologues of the nramp family of metal transporters.

    abstract::The baker's yeast Saccharomyces cerevisiae expresses three homologues of the Nramp family of metal transporters: Smf1p, Smf2p, and Smf3p, encoded by SMF1, SMF2, and SMF3, respectively. Here we report a comparative analysis of the yeast Smf proteins at the levels of localization, regulation, and function of the corresp...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Portnoy ME,Liu XF,Culotta VC

    更新日期:2000-11-01 00:00:00

  • Gata4 regulates testis expression of Dmrt1.

    abstract::The doublesex and mab-3 related transcription factor 1 (Dmrt1) is a putative transcriptional regulator that is expressed exclusively in the gonads and is required for postnatal testis differentiation. Here we describe the transcriptional mechanisms regulating testis-specific expression of the Dmrt1 gene. Transient-tra...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Lei N,Heckert LL

    更新日期:2004-01-01 00:00:00

  • Cellular Moloney murine sarcoma (c-mos) sequences are hypermethylated and transcriptionally silent in normal and transformed rodent cells.

    abstract::Moloney murine sarcoma virus carries an oncogenic sequence (v-mos) which is homologous to a single copy gene (c-mos) present in the normal cells of several vertebrate species. Because of the possible significance of c-mos sequences in normal development and malignant transformation induced by physical or chemical agen...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Gattoni S,Kirschmeier P,Weinstein IB,Escobedo J,Dina D

    更新日期:1982-01-01 00:00:00

  • A complex array of positive and negative elements regulates the chicken alpha A-crystallin gene: involvement of Pax-6, USF, CREB and/or CREM, and AP-1 proteins.

    abstract::The abundance of crystallins (> 80% of the soluble protein) in the ocular lens provides advantageous markers for selective gene expression during cellular differentiation. Here we show by functional and protein-DNA binding experiments that the chicken alpha A-crystallin gene is regulated by at least five control eleme...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Cvekl A,Sax CM,Bresnick EH,Piatigorsky J

    更新日期:1994-11-01 00:00:00

  • Conditional knockout mice reveal an essential role of protein phosphatase 4 in thymocyte development and pre-T-cell receptor signaling.

    abstract::Okadaic acid-sensitive serine/threonine phosphatases have been shown to regulate interleukin-2 transcription and T-cell activation. Okadaic acid inhibits protein phosphatase 4 (PP4), a novel PP2A-related serine/threonine phosphatase, at a 50% inhibitory concentration (IC(50)) comparable to that for PP2A. This raises t...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Shui JW,Hu MC,Tan TH

    更新日期:2007-01-01 00:00:00

  • Checkpoint-Independent Regulation of Origin Firing by Mrc1 through Interaction with Hsk1 Kinase.

    abstract::Mrc1 is a conserved checkpoint mediator protein that transduces the replication stress signal to the downstream effector kinase. The loss of mrc1 checkpoint activity results in the aberrant activation of late/dormant origins in the presence of hydroxyurea. Mrc1 was also suggested to regulate orders of early origin fir...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Matsumoto S,Kanoh Y,Shimmoto M,Hayano M,Ueda K,Fukatsu R,Kakusho N,Masai H

    更新日期:2017-03-17 00:00:00

  • snRNA 3' end formation requires heterodimeric association of integrator subunits.

    abstract::The Integrator Complex is a group of proteins responsible for the endonucleolytic cleavage of primary small nuclear RNA (snRNA) transcripts within the nucleus. Integrator subunits 9 and 11 (IntS9/11) are thought to contain the catalytic activity based on their high sequence similarity to CPSF100 and CPSF73, which have...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Albrecht TR,Wagner EJ

    更新日期:2012-03-01 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

  • Sequence identification of cytochrome b in Plasmodium gallinaceum.

    abstract::We have identified a gene that encodes the polypeptide cytochrome b in the avian malarial parasite Plasmodium gallinaceum. The gene containing the open reading frame was found to be located on a 6.2-kilobase multimeric extrachromosomal element. The amino acid translation from this gene demonstrated significant similar...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Aldritt SM,Joseph JT,Wirth DF

    更新日期:1989-09-01 00:00:00

  • Identification in vivo of different rate-limiting steps associated with transcriptional activators in the presence and absence of a GAGA element.

    abstract::We analyzed the impact of a GAGA element on a transgenic promoter in Drosophila melanogaster that was activated by proteins composed of the Tet(on) DNA binding domain and either the heat shock factor (HSF) activation domain or a potent subdomain of VP16. Permanganate footprinting was used to monitor polymerase II (Pol...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Wang YV,Tang H,Gilmour DS

    更新日期:2005-05-01 00:00:00

  • Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages.

    abstract::Apoptotic cells are swiftly engulfed by macrophages to prevent the release of noxious materials from dying cells. Apoptotic cells expose phosphatidylserine (PtdSer) on their surface, and macrophages engulf them by recognizing PtdSer using specific receptors and opsonins. Here, we found that mouse resident peritoneal m...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Nishi C,Toda S,Segawa K,Nagata S

    更新日期:2014-04-01 00:00:00

  • Cleavage of RNA hairpins mediated by a developmentally regulated CCCH zinc finger protein.

    abstract::Control of RNA turnover is a major, but poorly understood, aspect of gene regulation. In multicellular organisms, progress toward dissecting RNA turnover pathways has been made by defining some cis-acting sequences that function as either regulatory or cleavage targets (J. G. Belasco and G. Brawerman, Control of Messe...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Bai C,Tolias PP

    更新日期:1996-12-01 00:00:00

  • Induction of apoptosis by sphingoid long-chain bases in Aspergillus nidulans.

    abstract::Sphingolipid metabolism is implicated to play an important role in apoptosis. Here we show that dihydrosphingosine (DHS) and phytosphingosine (PHS), two major sphingoid bases of fungi, have potent fungicidal activity with remarkably high structural and stereochemical specificity against Aspergillus nidulans. In fact, ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Cheng J,Park TS,Chio LC,Fischl AS,Ye XS

    更新日期:2003-01-01 00:00:00

  • LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression.

    abstract::Transforming growth factor β1 (TGF-β1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-β1 expression. Devoid of a DNA-binding domain, FH...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Dahan J,Levillayer F,Xia T,Nouët Y,Werts C,Fanton d'Andon M,Adib-Conquy M,Cassard-Doulcier AM,Khanna V,Chen J,Tordjmann T,Buendia MA,Jouvion G,Wei Y

    更新日期:2017-05-02 00:00:00

  • Bradykinin B(2) receptor-mediated mitogen-activated protein kinase activation in COS-7 cells requires dual signaling via both protein kinase C pathway and epidermal growth factor receptor transactivation.

    abstract::The signaling routes linking G-protein-coupled receptors to mitogen-activated protein kinase (MAPK) may involve tyrosine kinases, phosphoinositide 3-kinase gamma (PI3Kgamma), and protein kinase C (PKC). To characterize the mitogenic pathway of bradykinin (BK), COS-7 cells were transiently cotransfected with the human ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Adomeit A,Graness A,Gross S,Seedorf K,Wetzker R,Liebmann C

    更新日期:1999-08-01 00:00:00

  • Conformational changes induced in the protein tyrosine kinase p72syk by tyrosine phosphorylation or by binding of phosphorylated immunoreceptor tyrosine-based activation motif peptides.

    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


    authors: Kimura T,Sakamoto H,Appella E,Siraganian RP

    更新日期:1996-04-01 00:00:00

  • A genetic analysis of the E2F1 gene distinguishes regulation by Rb, p107, and adenovirus E4.

    abstract::The cellular transcription factor E2F appears to be a target for the regulatory action of the retinoblastoma tumor suppressor gene product. The recent isolation of the E2F1 cDNA clone, which encodes a polypeptide with properties characteristic of E2F, has now allowed a more detailed analysis of the regulation of E2F f...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Cress WD,Johnson DG,Nevins JR

    更新日期:1993-10-01 00:00:00

  • Cloning of GT box-binding proteins: a novel Sp1 multigene family regulating T-cell receptor gene expression.

    abstract::Analysis of a T-cell antigen receptor (TCR) alpha promoter from a variable gene segment (V) revealed a critical GT box element which is also found in upstream regions of several V alpha genes, TCR enhancer, and regulatory elements of other genes. This element is necessary for TCR gene expression and binds several prot...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Kingsley C,Winoto A

    更新日期:1992-10-01 00:00:00

  • A conserved alpha-helical motif mediates the interaction of Sp1-like transcriptional repressors with the corepressor mSin3A.

    abstract::Sp1-like proteins are defined by three highly homologous C(2)H(2) zinc finger motifs that bind GC-rich sequences found in the promoters of a large number of genes essential for mammalian cell homeostasis. Here we report that TIEG2, a transforming growth factor beta-inducible Sp1-like protein with antiproliferative fun...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Zhang JS,Moncrieffe MC,Kaczynski J,Ellenrieder V,Prendergast FG,Urrutia R

    更新日期:2001-08-01 00:00:00

  • FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface.

    abstract::As revealed by intracellular pools of nonactive Fas (Apo-1), export of Fas to the cell surface is often impaired in human tumors, thereby inactivating Fas ligand-mediated apoptosis. Here, we demonstrate that association with Fas-associated phosphatase 1 (FAP-1) attenuates Fas export to the cell surface. Forced express...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Ivanov VN,Lopez Bergami P,Maulit G,Sato TA,Sassoon D,Ronai Z

    更新日期:2003-05-01 00:00:00

  • Loss of the Sall3 gene leads to palate deficiency, abnormalities in cranial nerves, and perinatal lethality.

    abstract::Members of the Spalt gene family encode putative transcription factors characterized by seven to nine C2H2 zinc finger motifs. Four genes have been identified in mice--Spalt1 to Spalt4 (Sall1 to Sall4). Spalt homologues are widely expressed in neural and mesodermal tissues during early embryogenesis. Sall3 is normally...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章


    authors: Parrish M,Ott T,Lance-Jones C,Schuetz G,Schwaeger-Nickolenko A,Monaghan AP

    更新日期:2004-08-01 00:00:00