Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta family of cytokines. The recent observation that BMPs can inhibit breast cancer cell proliferation in vitro suggests that BMPs or the BMP pathway may hold promise as therapeutic targets for the control of breast tumor growth in women. Better to understand the mechanism of BMP-induced growth arrest we examined the effect of BMP-2 and mediators of BMP-2 action on cell proliferation and p21(Cip1) expression in breast cancer cell lines. We show here that BMP-2 potently inhibited the proliferation of breast cancer cell lines that express both Smad1 and Smad4 (CAMA-1, MCF7, MDA-MB-231, T-47D, ZR-75-1), but not that of cells that only express Smad1 (MDA-MB-468). Growth inhibition correlated with up-regulation of p21 mRNA and protein levels. Up-regulation of p21 was resistant to cycloheximide but not to actinomycin D, suggesting that it occurred at the transcriptional level. Using p21 promoter-luciferase reporter constructs we mapped the BMP-responsive region of the p21 promoter to within 211 base pairs of the transcription start site. Induction of p21 promoter activity was rapid and coincided with up-regulation of p21 mRNA and protein levels. p21 promoter activity required both Smad1 and Smad4 and was induced by either BMP-2 or constitutively active type I BMP receptors. Moreover, the C-terminal SSVS region of Smad1 was necessary for activation of the p21 promoter by BMP-2. Taken together, these results indicate that the mechanism of BMP-induced p21 promoter activation involves BMP receptors and BMP Smads.

This article has been cited by other articles:

				C. S. Tremblay, C. C. Huard, F.-F. Huang, O. Habi, V. Bourdages, G. Levesque, and M. Carreau The Fanconi Anemia Core Complex Acts as a Transcriptional Co-regulator in Hairy Enhancer of Split 1 Signaling J. Biol. Chem., May 15, 2009; 284(20): 13384 - 13395. [Abstract] [Full Text] [PDF]

				D. Su, S. Zhu, X. Han, Y. Feng, H. Huang, G. Ren, L. Pan, Y. Zhang, J. Lu, and B. Huang BMP4-Smad Signaling Pathway Mediates Adriamycin-induced Premature Senescence in Lung Cancer Cells J. Biol. Chem., May 1, 2009; 284(18): 12153 - 12164. [Abstract] [Full Text] [PDF]

				D. Zhu, J. Wu, C. Spee, S. J. Ryan, and D. R. Hinton BMP4 Mediates Oxidative Stress-induced Retinal Pigment Epithelial Cell Senescence and Is Overexpressed in Age-related Macular Degeneration J. Biol. Chem., April 3, 2009; 284(14): 9529 - 9539. [Abstract] [Full Text] [PDF]

				S. M. BOKOBZA, L. YE, H. E. KYNASTON, R. E. MANSEL, and W. G. JIANG Reduced Expression of BMPR-IB Correlates with Poor Prognosis and Increased Proliferation of Breast Cancer Cells Cancer Genomics Proteomics, March 1, 2009; 6(2): 101 - 108. [Abstract] [Full Text] [PDF]

				M. Takahashi, F. Otsuka, T. Miyoshi, H. Otani, J. Goto, M. Yamashita, T. Ogura, H. Makino, and H. Doihara Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation J. Endocrinol., December 1, 2008; 199(3): 445 - 455. [Abstract] [Full Text] [PDF]

				K. R. Blish, W. Wang, M. C. Willingham, W. Du, C. E. Birse, S. R. Krishnan, J. C. Brown, G. A. Hawkins, A. J. Garvin, R. B. D'Agostino Jr., et al. A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer Mol. Biol. Cell, February 1, 2008; 19(2): 457 - 464. [Abstract] [Full Text] [PDF]

				S. A. Pangas, X. Li, L. Umans, A. Zwijsen, D. Huylebroeck, C. Gutierrez, D. Wang, J. F. Martin, S. P. Jamin, R. R. Behringer, et al. Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in Mice Mol. Cell. Biol., January 1, 2008; 28(1): 248 - 257. [Abstract] [Full Text] [PDF]

				H. J. Lee, Y. Ji, S. Paul, H. Maehr, M. Uskokovic, and N. Suh Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase C{alpha} Cancer Res., December 15, 2007; 67(24): 11840 - 11847. [Abstract] [Full Text] [PDF]

				S. E. Beck, B. H. Jung, A. Fiorino, J. Gomez, E. D. Rosario, B. L. Cabrera, S. C. Huang, J. Y. C. Chow, and J. M. Carethers Bone morphogenetic protein signaling and growth suppression in colon cancer. Am J Physiol Gastrointest Liver Physiol, July 1, 2006; 291(1): G135 - G145. [Abstract] [Full Text] [PDF]

				H. J. Lee, A. Wislocki, C. Goodman, Y. Ji, R. Ge, H. Maehr, M. Uskokovic, M. Reiss, and N. Suh A Novel Vitamin D Derivative Activates Bone Morphogenetic Protein Signaling in MCF10 Breast Epithelial Cells Mol. Pharmacol., June 1, 2006; 69(6): 1840 - 1848. [Abstract] [Full Text] [PDF]

				T. K. Jeffery, P. D. Upton, R. C. Trembath, and N. W. Morrell BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L370 - L378. [Abstract] [Full Text] [PDF]

				S. Buckley, W. Shi, B. Driscoll, A. Ferrario, K. Anderson, and D. Warburton BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L81 - L86. [Abstract] [Full Text] [PDF]

				H. Qi, A. Fournier, J. Grenier, C. Fillion, Y. Labrie, and C. Labrie Isolation of the Novel Human Guanine Nucleotide Exchange Factor Src Homology 3 Domain-Containing Guanine Nucleotide Exchange Factor (SGEF) and of C-Terminal SGEF, an N-Terminally Truncated Form of SGEF, the Expression of Which Is Regulated by Androgen in Prostate Cancer Cells Endocrinology, May 1, 2003; 144(5): 1742 - 1752. [Abstract] [Full Text] [PDF]

				F. Pouliot, A. Blais, and C. Labrie Overexpression of a Dominant Negative Type II Bone Morphogenetic Protein Receptor Inhibits the Growth of Human Breast Cancer Cells Cancer Res., January 15, 2003; 63(2): 277 - 281. [Abstract] [Full Text] [PDF]