Cell Growth & Differentiation, Vol 7, Issue 3 289-300, Copyright © 1996 by American Association of Cancer Research

ARTICLES

Gamma-interferon induces an irreversible growth arrest in mid-G1 in mammary epithelial cells which correlates with a block in hyperphosphorylation of retinoblastoma

BL Harvat and AM Jetten
National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.

In this study, we analyze effects of IFN-gamma on the proliferation of normal human mammary epithelial cells (MECs) and several mammary carcinoma cell lines. We demonstrate that IFN-gamma blocks the proliferation of MECs in a time- and concentration-dependent manner. This growth arrest is irreversible and occurs at a specific stage in the G1 phase of the cell cycle. IFN-gamma caused a rapid (within 12-24 h) down-regulation of cyclin A, c-myc, and cdc2 proteins, as well as a disappearance of hyperphosphorylated forms of the retinoblastoma family proteins, Rb and p130. The synthesis of several other growth control proteins, p53, p21/Waf1, and proliferating cell nuclear antigen, was down-regulated between 24 and 48 h. In MECs synchronized by epidermal growth factor deprivation and released for cell cycle traverse by re-addition of epidermal growth factor to the medium, IFN-gamma was able to block DNA synthesis only if added in the first 6 to 7 h after epidermal growth factor. The block in Rb phosphorylation and cyclin A expression was coordinately regulated during the same narrow window of G1. Several mammary carcinoma cell lines demonstrated resistance to the growth-inhibitory effects of IFN-gamma and did not exhibit down-regulation of cdc2 and cyclin A expression or a change in hyperphosphorylation of Rb when treated with IFN-gamma. Initial studies suggest, in some carcinoma cell lines, that resistance to IFN-gamma may be caused by defects in the IFN-gamma signal transduction pathway (measured by expression of the IFN-gamma-responsive gene GBP), while resistance in others may be due to defects in cell cycle regulatory proteins that are the targets of IFN-gamma action.

This article has been cited by other articles:

				S. J. Prasanna, B. Saha, and D. Nandi Involvement of oxidative and nitrosative stress in modulation of gene expression and functional responses by IFN{gamma} Int. Immunol., July 2, 2007; (2007) dxm058v1. [Abstract] [Full Text] [PDF]

				O. Moiseeva, F. A. Mallette, U. K. Mukhopadhyay, A. Moores, and G. Ferbeyre DNA Damage Signaling and p53-dependent Senescence after Prolonged beta-Interferon Stimulation Mol. Biol. Cell, April 1, 2006; 17(4): 1583 - 1592. [Abstract] [Full Text] [PDF]

				L.-C. Wang, C. Y. Okitsu, and E. Zandi Tumor Necrosis Factor {alpha}-dependent Drug Resistance to Purine and Pyrimidine Analogues in Human Colon Tumor Cells Mediated through IKK J. Biol. Chem., March 4, 2005; 280(9): 7634 - 7644. [Abstract] [Full Text] [PDF]

				K. Schroder, P. J. Hertzog, T. Ravasi, and D. A. Hume Interferon-{gamma}: an overview of signals, mechanisms and functions J. Leukoc. Biol., February 1, 2004; 75(2): 163 - 189. [Abstract] [Full Text] [PDF]

				S. Ilangumaran, D. Finan, J. La Rose, J. Raine, A. Silverstein, P. De Sepulveda, and R. Rottapel A Positive Regulatory Role for Suppressor of Cytokine Signaling 1 in IFN-{gamma}-Induced MHC Class II Expression in Fibroblasts J. Immunol., November 1, 2002; 169(9): 5010 - 5020. [Abstract] [Full Text] [PDF]

				J. A. Hutt and J. W. DeWille Oncostatin M Induces Growth Arrest of Mammary Epithelium via a CCAAT/enhancer-binding Protein {delta}-dependent Pathway Mol. Cancer Ther., June 1, 2002; 1(8): 601 - 610. [Abstract] [Full Text] [PDF]

				K M Detjen, K Farwig, M Welzel, B Wiedenmann, and S Rosewicz Interferon {gamma} inhibits growth of human pancreatic carcinoma cells via caspase-1 dependent induction of apoptosis Gut, August 1, 2001; 49(2): 251 - 262. [Abstract] [Full Text] [PDF]

				J. L. Gooch, R. E. Herrera, and D. Yee The Role of p21 in Interferon {{gamma}}-mediated Growth Inhibition of Human Breast Cancer Cells Cell Growth Differ., June 1, 2000; 11(6): 335 - 342. [Abstract] [Full Text]

				H. Matsuura, M. Sakaue, K. Subbaramaiah, H. Kamitani, T. E. Eling, A. J. Dannenberg, T. Tanabe, H. Inoue, J. Arata, and A. M. Jetten Regulation of Cyclooxygenase-2 by Interferon gamma and Transforming Growth Factor alpha in Normal Human Epidermal Keratinocytes and Squamous Carcinoma Cells. ROLE OF MITOGEN-ACTIVATED PROTEIN KINASES J. Biol. Chem., October 8, 1999; 274(41): 29138 - 29148. [Abstract] [Full Text] [PDF]

				M. D. S. Jean, F. Brignole, G. Feldmann, A. Goguel, and C. Baudouin Interferon-{gamma} Induces Apoptosis and Expression of Inflammation-Related Proteins in Chang Conjunctival Cells Invest. Ophthalmol. Vis. Sci., September 1, 1999; 40(10): 2199 - 2212. [Abstract] [Full Text] [PDF]

				Y.-J. Lee and C. H. Streuli Extracellular Matrix Selectively Modulates the Response of Mammary Epithelial Cells to Different Soluble Signaling Ligands J. Biol. Chem., August 6, 1999; 274(32): 22401 - 22408. [Abstract] [Full Text] [PDF]

				C. M. Perou, S. S. Jeffrey, M. van de Rijn, C. A. Rees, M. B. Eisen, D. T. Ross, A. Pergamenschikov, C. F. Williams, S. X. Zhu, J. C. F. Lee, et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers PNAS, August 3, 1999; 96(16): 9212 - 9217. [Abstract] [Full Text] [PDF]

				N. E. S. Sibinga, H. Wang, M. A. Perrella, W. O. Endege, C. Patterson, M. Yoshizumi, E. Haber, and M.-E. Lee Interferon-{gamma}-mediated Inhibition of Cyclin A Gene Transcription Is Independent of Individual cis-Acting Elements in the Cyclin A Promoter J. Biol. Chem., April 23, 1999; 274(17): 12139 - 12146. [Abstract] [Full Text] [PDF]

				Y. Kronfeld-Kinar, S. Vilchik, T. Hyman, F. Leibkowicz, and S. Salzberg Involvement of PKR in the Regulation of Myogenesis Cell Growth Differ., March 1, 1999; 10(3): 201 - 212. [Abstract] [Full Text]

				H. Adachi, G. Preston, B. Harvat, M. I. Dawson, and A. M. Jetten Inhibition of Cell Proliferation and Induction of Apoptosis by the Retinoid AHPN in Human Lung Carcinoma Cells Am. J. Respir. Cell Mol. Biol., March 1, 1998; 18(3): 323 - 333. [Abstract] [Full Text]

				B. Harvat, A Wang, P Seth, and A. Jetten Up-regulation of p27Kip1, p21WAF1/Cip1 and p16Ink4a is associated with, but not sufficient for, induction of squamous differentiation J. Cell Sci., January 5, 1998; 111(9): 1185 - 1196. [Abstract] [PDF]