title: NFBD1/MDC1 regulates Cav1 and Cav2 independently of DNA damage and p53.
abstract: NFBD1/MDC1 is involved in DNA damage checkpoint signaling and DNA repair. NFBD1 binds to the chromatin component γH2AX at sites of DNA damage, causing amplification of ataxia telangiectasia-mutated gene (ATM) pathway signaling and recruitment of DNA repair factors. Residues 508-995 of NFBD1 possess transactivation activity, suggesting a possible role of NFBD1 in transcription. Furthermore, NFBD1 influences p53-mediated transcription in response to adriamycin. We sought to determine the role of NFBD1 in ionizing radiation (IR)-responsive transcription and if NFBD1 influences transcription independently of p53. Using microarray analysis, we identified genes altered upon NFBD1 knockdown. Surprisingly, most NFBD1 regulated genes are regulated in both the absence and presence of IR, thus pointing toward a novel function for NFBD1 outside of the DNA damage response. Furthermore, NFBD1 knockdown regulated genes mostly independent of p53 knockdown. These genes are involved in pathways including focal adhesion signaling, carbohydrate metabolism, and insulin signaling. We found that CAV1 and CAV2 mRNA and protein levels are reduced by both NFBD1 knockdown and knockout independently of IR and p53. NFBD1-depleted cells exhibit some similar phenotypes to Cav1-depleted cells. Furthermore, like Cav1-depletion, NFBD1 shRNA increases Erk phosphorylation. Thus, Cav1 could act as a mediator of the DNA-damage independent effects of NFBD1 in mitogenic signaling.
authors.affiliation: Yale University, 333 Cedar Street, P.O. Box 208023, New Haven, CT 06520, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Wilson
authors.forename: Sierra A
authors.initials: SA
authors.lastname: Colavito
authors.forename: Vincent
authors.initials: V
authors.lastname: Schulz
authors.forename: Patricia Heffernan
authors.initials: PH
authors.lastname: Wakefield
authors.forename: William
authors.initials: W
authors.lastname: Sessa
authors.forename: David
authors.initials: D
authors.lastname: Tuck
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D051242:Caveolin 1 / Q000378:metabolism*; D051243:Caveolin 2 / Q000378:metabolism*; D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495540:CAV1 protein, human; C495544:CAV2 protein, human; D051242:Caveolin 1; D051243:Caveolin 2; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases