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Expression and transactivating functions of the bZIP transcription factor GADD153 in mammary epithelial cells

Oncogene volume 21, pages 4289–4300 (2002)Cite this article

Abstract

Heregulin-β1 (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 β-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.

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Abbreviations

HRG:

heregulin-β1

HER:

Human EGF Receptor

HCT:

anti-HER2 antibody herceptin

RT–PCR:

reverse transcriptase polymerase chain reaction

ATF:

activating transcription factor

bZIP:

basic leucine zipper

CRE:

cAMP response element

CREB:

CRE-binding protein

CBP:

CREB-binding protein

GADD:

growth arrest and DNA damage-inducible protein

Dex:

dexamethasone

C/EBP:

CCAAT -enhancer -binding protein

CHOP:

C/EBP homologous protein

NBT:

nitro blue tetrazolium

BCIP:

5-bromo-4-chloro-3-indolyl phosphate

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Acknowledgements

This study was supported in part by NIH grants CA80066 and CA65746, and Bristol Mayer Research Program Grant (R Kumar). We are grateful to Nikki J Holbrook for GADD153-CAT and GADD153-luci, Jeffrey Rosen for β-Casein-Luci and STAT5a constructs, David Stern for the HER2 constructs, Toshio Kitamura for STAT5 constructs, Joel F Habener for ATF4 cDNA, Shizuo Akira for ATF4, Mien Chie Hung for NIH3T3/HER2NT cells, and Genetal for Hesceptin. We thank Daniel Medina for the HC11 cells, Ratna Vadlamudi for helpful discussions.

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  1. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Amjad H Talukder, Rui-An Wang & Rakesh Kumar

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  1. Amjad H Talukder
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Correspondence to Rakesh Kumar.

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Talukder, A., Wang, RA. & Kumar, R. Expression and transactivating functions of the bZIP transcription factor GADD153 in mammary epithelial cells. Oncogene 21, 4289–4300 (2002). https://doi.org/10.1038/sj.onc.1205529

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