Expression and transactivating functions of the bZIP transcription factor GADD153 in mammary epithelial cells.
Heregulin-beta1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 (HER3) and HER4, is a regulatory polypeptide having distinct biological effects, such as growth stimulation, differentiation, invasiveness, and migration in mammary epithelial cells. The mechanism underlying the diverse functions of HRG is not well established but is believed to depend on induced changes in the expression of specific cellular gene products, their modification, or both. Here, we identified the basic leucine zipper transcription factor, the growth-arrest and DNA-damage 153 (GADD153)/CCAAT-enhancer binding protein (C/EBP) homologous protein (CHOP) as one of the HRG-inducible genes. We demonstrated that HRG stimulation of mammary epithelial cells induces the expression of GADD153 mRNA and protein and transcription of GADD153 promoter. The transcriptional activity of the GADD153 promoter as well as transcription from the C/EBP-activating transcription factor (ATF) composite motif in the GADD153 promoter was also stimulated by HRG-inducible ATF-4 and activated HER2 but not wild-type HER2. GADD153 expression was upregulated by the lactogenic hormones insulin and progesterone and associated with differentiation of normal mammary epithelial cells. Consistent with its role as transcriptional modifier, GADD153 stimulated transcription of beta-casein promoter activity in a STAT5a-sensitive manner in mammary epithelial cells. Analysis of mouse mammary gland development revealed that GADD153 expression was predominantly restricted in the early lactating stages. Because cyclic AMP responsive element and ATF binding sites are present in a variety of growth-regulating cellular genes, these findings suggest that stimulation of GADD153 expression and its transactivating functions may constitute an important mechanism of regulation of putative genes having diverse functions during cell growth and differentiation.
Talukder
Amjad H
AH
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Wang
Rui-An
RA
Kumar
Rakesh
R
D051701:Activating Transcription Factor 4; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001940:Breast / Q000166:cytology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002364:Caseins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018734:Genes, erbB-2; D006801:Humans; D017403:In Situ Hybridization; D007328:Insulin / Q000494:pharmacology; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008894:Milk Proteins; D020890:Neuregulin-1 / Q000502:physiology*; D011374:Progesterone / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D051701:Activating Transcription Factor 4; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D022762:CCAAT-Enhancer-Binding Proteins; D002364:Caseins; D000242:Cyclic AMP; D004268:DNA-Binding Proteins; D007328:Insulin; D008894:Milk Proteins; D020890:Neuregulin-1; D011374:Progesterone; D018719:Erb-b2 Receptor Tyrosine Kinases; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins; C497109:ATF4 protein, human; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; C494092:STAT5A protein, human; C494093:Stat5a protein, mouse