|
|
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.
 Previous Article | Next Article 
Submitted August 18, 2005
Accepted January 21, 2006
Cul-4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis
Binghui Li, Nan Jia, Reuben Kapur, and Kristin T Chun*
Department of Pediatrics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
* Corresponding author; email: kchun{at}iupui.edu.
As erythroid progenitors differentiate into precursors and finally mature red blood cells, lineage-specific genes are induced, and proliferation declines until cell cycle exit. CUL-4A encodes a core subunit of a ubiquitin ligase that targets proteins for ubiquitin-mediated degradation, and CUL-4A 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 CUL-4A+/- mice. Conversely, overexpression of CUL-4A 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 CUL-4A 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 CUL-4A enforced expression destabilized p27 and attenuated its accumulation. CUL-4A and p27 proteins coimmunoprecipitate, indicating that a Cul-4A ubiquitin ligase targets p27 for degradation. These findings indicate that a Cul-4A ubiquitin ligase positively regulates proliferation by targeting p27 for degradation and that CUL-4A 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:
|
|
|
|
 
Y. Zou, J. Mi, J. Cui, D. Lu, X. Zhang, C. Guo, G. Gao, Q. Liu, B. Chen, C. Shao, et al.
Characterization of Nuclear Localization Signal in the N Terminus of CUL4B and Its Essential Role in Cyclin E Degradation and Cell Cycle Progression
J. Biol. Chem.,
November 27, 2009;
284(48):
33320 - 33332.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. Miranda-Carboni, S. A. Krum, K. Yee, M. Nava, Q. E. Deng, S. Pervin, A. Collado-Hidalgo, Z. Galic, J. A. Zack, K. Nakayama, et al.
A functional link between Wnt signaling and SKP2-independent p27 turnover in mammary tumors
Genes & Dev.,
November 15, 2008;
22(22):
3121 - 3134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
