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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4291-4299. Prepublished online as a Blood First Edition Paper on February 7, 2006; DOI 10.1182/blood-2005-08-3349. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-08-3349v1 107/11/4291    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Li, B. Articles by Chun, K. T. Search for Related Content PubMed PubMed Citation Articles by Li, B. Articles by Chun, K. T. Related Collections Hematopoiesis and Stem Cells Cell Cycle Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Cul4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis Binghui Li, Nan Jia, Reuben Kapur, and Kristin T. Chun From the Herman B Wells Center for Pediatric Research, Department of Pediatrics; and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN. As erythroid progenitors differentiate into precursors and finally mature red blood cells, lineage-specific genes are induced, and proliferation declines until cell cycle exit. Cul4A encodes a core subunit of a ubiquitin ligase that targets proteins for ubiquitin-mediated degradation, and Cul4A-haploinsufficient mice display hematopoietic dysregulation with fewer multipotential and erythroid-committed progenitors. In this study, stress induced by 5-fluorouracil or phenylhydrazine revealed a delay in the recovery of erythroid progenitors, early precursors, and normal hematocrits in Cul4A+/– mice. Conversely, overexpression of Cul4A in a growth factor-dependent, proerythroblast cell line increased proliferation and the proportion of cells in S phase. When these proerythroblasts were induced to terminally differentiate, endogenous Cul4A protein expression declined 3.6-fold. Its enforced expression interfered with erythrocyte maturation and cell cycle exit and, instead, promoted proliferation. Furthermore, p27 normally accumulates during erythroid terminal differentiation, but Cul4A-enforced expression destabilized p27 and attenuated its accumulation. Cul4A and p27 proteins coimmunoprecipitate, indicating that a Cul4A ubiquitin ligase targets p27 for degradation. These findings indicate that a Cul4A ubiquitin ligase positively regulates proliferation by targeting p27 for degradation and that Cul4A down-regulation during terminal erythroid differentiation allows p27 to accumulate and signal cell cycle exit. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. L. Waning, B. Li, N. Jia, Y. Naaldijk, W. S. Goebel, H. HogenEsch, and K. T. Chun Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis Blood, July 15, 2008; 112(2): 320 - 329. [Abstract] [Full Text] [PDF] C. Klijn, H. Holstege, J. de Ridder, X. Liu, M. Reinders, J. Jonkers, and L. Wessels Identification of cancer genes using a statistical framework for multiexperiment analysis of nondiscretized array CGH data Nucleic Acids Res., February 2, 2008; 36(2): e13 - e13. [Abstract] [Full Text] [PDF] L. Tan, E. Ehrlich, and X.-F. Yu DDB1 and Cul4A Are Required for Human Immunodeficiency Virus Type 1 Vpr-Induced G2 Arrest J. Virol., October 1, 2007; 81(19): 10822 - 10830. [Abstract] [Full Text] [PDF] B. Li, N. Jia, D. L. Waning, F.-C. Yang, L. S. Haneline, and K. T. Chun Cul4A is required for hematopoietic stem-cell engraftment and self-renewal Blood, October 1, 2007; 110(7): 2704 - 2707. [Abstract] [Full Text] [PDF]

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