This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rooney, R. J. Search for Related Content PubMed PubMed Citation Articles by Rooney, R. J.

Cell Cycle Attenuation by p120E4F Is Accompanied by Increased Mitotic Dysfunction¹

Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710

In addition to their well-established roles at the G₁-S checkpoint, recent reports support a role for universal cyclin-dependent kinase (CDK) inhibitors in the control of G₂-M and suggest that their induction may stimulate the occurrence of endomitosis or polyploidy in a number of physiological settings. In this report, the stable expression of the p120E4F transcription factor, which attenuates G₁-S progression by elevating p21^WAF1 and p27^KIP1 protein levels, was shown to also interfere with the regulation of G₂-M and cytokinesis. Exponentially growing cultures of p120E4F-expressing fibroblast cell lines had reduced levels of CDC2 kinase activity, elevated levels of Cyclin B1 protein, and continuously generated a subpopulation of tetraploid cells and elevated numbers of multinucleated cells. Coexpression of activated Ras, which stimulates Cyclin D1 expression and G₁-S-specific cyclin-CDK kinase activities, alleviated these effects without reducing p21^WAF1 or p27^KIP1 protein levels; p120E4F/ras-expressing cell lines contained reduced levels of Cyclin B1 protein, a restoration of Cyclin B-CDC2 kinase activity to control levels, and exhibited no increase of tetraploid or multinucleated cells. Interestingly, changes in the expression of Cyclin B1 and, to a lesser extent, CDC2 were primarily regulated by post-transcriptional mechanisms. The results indicate that mechanisms which moderately elevate CDK inhibitor levels can reduce CDC2 kinase activity to the point of impeding normal G₂-M function and suggest that two molecular determinants commonly associated with the induction of polyploidy in a number of tissues, i.e., elevated levels of universal CDK inhibitors and sustained CDK2 kinase activity, may be solely sufficient to initiate endomitosis.

This article has been cited by other articles:

				J. Chagraoui, S. L. Niessen, J. Lessard, S. Girard, P. Coulombe, M. Sauvageau, S. Meloche, and G. Sauvageau E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells Genes & Dev., August 1, 2006; 20(15): 2110 - 2120. [Abstract] [Full Text] [PDF]

				Y. Nakamura, K. Igarashi, T. Suzuki, J. Kanno, T. Inoue, C. Tazawa, M. Saruta, T. Ando, N. Moriyama, T. Furukawa, et al. E4F1, a Novel Estrogen-Responsive Gene in Possible Atheroprotection, Revealed by Microarray Analysis Am. J. Pathol., December 1, 2004; 165(6): 2019 - 2031. [Abstract] [Full Text] [PDF]

				L. Le Cam, M. Lacroix, M. A. Ciemerych, C. Sardet, and P. Sicinski The E4F Protein Is Required for Mitotic Progression during Embryonic Cell Cycles Mol. Cell. Biol., July 15, 2004; 24(14): 6467 - 6475. [Abstract] [Full Text] [PDF]

				S. L. Fenton, A. Dallol, A. Agathanggelou, L. Hesson, J. Ahmed-Choudhury, S. Baksh, C. Sardet, R. Dammann, J. D. Minna, J. Downward, et al. Identification of the E1A-Regulated Transcription Factor p120E4F as an Interacting Partner of the RASSF1A Candidate Tumor Suppressor Gene Cancer Res., January 1, 2004; 64(1): 102 - 107. [Abstract] [Full Text] [PDF]

				M. A. Tessari, M. Gostissa, S. Altamura, R. Sgarra, A. Rustighi, C. Salvagno, G. Caretti, C. Imbriano, R. Mantovani, G. Del Sal, et al. Transcriptional Activation of the Cyclin A Gene by the Architectural Transcription Factor HMGA2 Mol. Cell. Biol., December 15, 2003; 23(24): 9104 - 9116. [Abstract] [Full Text] [PDF]

				H. Rizos, E. Diefenbach, P. Badhwar, S. Woodruff, T. M. Becker, R. J. Rooney, and R. F. Kefford Association of p14ARF with the p120E4F Transcriptional Repressor Enhances Cell Cycle Inhibition J. Biol. Chem., February 7, 2003; 278(7): 4981 - 4989. [Abstract] [Full Text] [PDF]

				R.-L. Xie, A. J. van Wijnen, C. M. van der Meijden, J. L. Stein, and G. S. Stein Forced Expression of the Interferon Regulatory Factor 2 Oncoprotein Causes Polyploidy and Cell Death in FDC-P1 Myeloid Hematopoietic Progenitor Cells Cancer Res., May 1, 2002; 62(9): 2510 - 2515. [Abstract] [Full Text] [PDF]