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
References
Adam L, Vadlamudi RK, Kondapaka S, Chernoff J, Mendelsohn J, Kumar R . 1998 J. Biol. Chem. 273: 28238–28246
Ariyoshi K, Nosaka T, Yamada K, Onishi M, Oka Y, Miyajima A, Kitamura T . 2000 J. Biol. Chem. 275: 24407–24413
Batchvarona N, Wang X-Y, Ron D . 1995 EMBO J. 14: 4654–4661
Barone MV, Crozat A, Tabae A, Philipson L, Ron D . 1994 Genes Dev. 8: 453–464
Burden S, Yarden Y . 1997 Neuron 18: 847–855
Carraway K, Cantley L . 1994 Cell 78: 5–8
Cao Z, Umek RM, McKnight SL . 1991 Genes Dev. 5: 1538–1552
Chen BP, Wolfgang CD, Hai T . 1996 Mol. Cell. Biol. 16: 1157–1168
Coutts M, Cui K, Davis KL, Keutzer JC, Sytkowski AJ . 1999 Blood 93: 3369–3378
Crozat A, Aman P, Mandahl N, Ron D . 1993 Nature 363: 640–644
Cui K, Coutts M, Stahl J, Sytkowski AJ . 2000 J. Biol. Chem. 275: 7591–7596
Fawcett TW, Eastman HB, Martindale JL, Holbrook NJ . 1996 J. Biol. Chem. 271: 14285–14289
Fawcett TW, Martindale JL, Guyton KZ, Hai T, Holbrook NJ . 1999 Biochem. J. 339: 135–141
Fitzpatrick VD, Pisacane PI, Vandlen RL, Sliwkowski MX . 1998 FEBS Lett. 431: 102–106
Fornace Jr AJ, Nebert DW, Hollander MC, Luethy JD, Papathanasiou M, Fargnoli J, Holbrook NJ . 1989 Mol. Cell. Biol. 9: 4196–4203
Goodrich JA, Cutler G, Tjian R . 1996 Cell 84: 825–830
Hennighausen L, Robinson GW . 1998 Genes Dev. 12: 449–455
Huang Q, Lau SS, Monks TJ . 1999 Biochem. J. 341: 225–231
Hynes NC, Stern DF . 1994 Biochim. Biophys. Acta. 1198: 165–184
Janknecht R, Hunter T . 1996 Curr. Biol. 6: 951–954
Jones FE, Joseph Jerry D, Guarino BC, Andrews GC, Stern DF . 1996 Cell Growth Diff. 7: 1031–1038
Kazansky AV, Kabotyanski EB, Wyszomierski SL, Mancini MA, Rosen JM . 1999 J. Biol. Chem. 274: 22484–22492
Krane IM, Leder P . 1996 Oncogene 12: 1781–1788
Kumar R, Mandal M, Lipton A, Harvey H, Thompson CB . 1996 Clin. Can. Res. 2: 1215–1219
Marte BM, Jeschke M, Graus-Porta D, Hofer P, Groner B, Yarden Y, Hynes NE . 1995 Mol. Endocrinol. 9: 14–23
Matsumoto M, Minami M, Takeda K, Sakao Y, Akira S . 1996 FEBS Lett. 395: 143–147
MacLachlan TK, Somasundaram K, Sgagias M, Shifman Y, Muschel RJ, Cowen KH, El-Deiry WS . 2000 J. Biol. Chem. 275: 2777–2785
Mandal M, Vadlamudi R, Nguyen D, Wang R, Costa L, Bagheri-Yarmand R, Mendelsohn J, Kumar R . 2001 J. Biol. Chem. 276: 9699–9704
Mazumdar A, Wang RW, Mishra SK, Adam L, Yarmand RB, Mandal M, Vadlamudi R, Kumar R . 2001 Nature Cell Biol. 3: 30–37
Park JS, Luethy JD, Wang MG, Fargnoli J, Fornace Jr AJ, McBride OW, Holbrook NJ . 1992 Gene 116: 259–267
Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Levy RB, Yarden Y . 1992 Cell 69: 205–216
Reese DM, Slamon DJ . 1997 Stem Cells 15: 1–8
Ron D, Habener JF . 1992 Genes Dev. 6: 439–453
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . 1987 Science 235: 77–82
Talukder AH, Mandal M, Vadlamudi RV, Mendelsohn J, Kumar R . 2001 J. Biol. Chem. 276: 5636–5642
Talukder AH, Vadlamudi R, Mandal M, Kumar R . 2000 Cancer Res. 60: 276–281
Ubeda M, Wang XZ, Zinszner H, Wu HI, Habener JF, Ron D . 1996 Mol. Cell. Biol. 16: 1479–1489
Vadlamudi R, Mandal M, Adam L, Bandyopadhyay D, Steinbach G, Mendelsohn J, Kumar R . 1999 Oncogene 18: 305–314
Vadlamudi R, Wang R, Talukder AH, Adam L, Johnson R, Kumar R . 2000 Mol. Cell. Biol. 20: 9092–9101
Verrijzer CP, Tjian R . 1996 Trends Biochem. Sci. 21: 338–342
Vinson CR, Hai T, Boyd SM . 1993 Genes Dev. 7: 1047–1058
Wolfgang CD, Chen BPC, Martindale JL, Holbrook NJ, Hai T . 1997 Mol. Cell. Biol. 17: 6700–6707
Xie Y, Pendergast AM, Hung MC . 1995 J. Biol. Chem. 270: 30717–30724
Yang Y, Spitzer E, Meyer D, Sachs M, Neimann C, Hartmann G, Weidner KM, Birchmeier C, Birchmeier W . 1995 J. Cell. Biol. 131: 215–226
Zhan Q, Lord KA, Alamo I, Hollander CM, Carrier F, Ron D, Kohn KW, Hoffman B, Liebermann DA, Fornace Jr AJ . 1994 Mol. Cell. Biol. 14: 2361–2371
Zinszer H, Kuroda M, Wang X, Batchvarova N, Lightfoot R, Remotti H, Stevens J, Ron D . 1998 Genes Dev. 12: 982–995
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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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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DOI: https://doi.org/10.1038/sj.onc.1205529
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