Published online before print August 1, 2002, doi: 10.1161/01.RES.0000031744.06353.D3
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on June 4, 2002
Revised on July 18, 2002
Accepted on July 22, 2002
Functionally Novel Tumor Necrosis Factor-
--Modulated CHR-Binding Protein Mediates Cyclin A Transcriptional Repression in Vascular Endothelial Cells
Raj Kishore ;
From the Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass.
* To whom correspondence should be addressed. E-mail: douglas.losordo{at}tufts.edu.
Local expression of tumor necrosis factor- (TNF-) at the sites of arterial injury after balloon angioplasty, suppresses endothelial cell (EC) proliferation and negatively affects reendothelialization of the injured vessel. We have previously reported that in vitro exposure of ECs to TNF- induced EC growth arrest and apoptosis. These effects were mediated, at least in part, by downregulation of cell cycle regulatory proteins. In the present study, we report potential mechanism(s) for TNF---mediated suppression of cyclin A in ECs. TNF- exposure to ECs completely abrogated cyclin A mRNA expression via mechanisms involving both transcriptional and posttranscriptional modifications. TNF- inhibited de novo cyclin A mRNA synthesis and suppressed cyclin A promoter activity. Utilizing deletion mutants of human cyclin A promoter, we have identified CDE-CHR (Cell cycle--Dependent Elements--Cell cycle genes Homology Region) region of cyclin A promoter as a target for TNF- suppressive action. Experiments to investigate CDE-CHR binding proteins/factors revealed a TNF---mediated increase in specific DNA binding activity to the CHR elements. This increase in binding activity by TNF- was mediated via the induction of a functionally novel 84-kDa protein that binds specifically to CHR in Southwestern assays. UV cross-linking and SDS-PAGE analysis of proteins eluted from specific complex confirmed the presence of this 84-kDa protein. Moreover, induction of this protein by TNF- was protein synthesis dependent. Additionally, exposure of ECs to TNF- markedly reduced cyclin A mRNA stability. Targeted disruption of this protein could potentially be a therapeutic strategy to rescue EC proliferation in vivo.
Key words: endothelial cells • tumor necrosis factor-
•
cell cycle--dependent elements •
cell cycle gene homology region
This article has been cited by other articles:
 |
|
 |
|
  H. Hamada, M. K. Kim, A. Iwakura, M. Ii, T. Thorne, G. Qin, J. Asai, Y. Tsutsumi, H. Sekiguchi, M. Silver, et al. Estrogen Receptors {alpha} and {beta} Mediate Contribution of Bone Marrow-Derived Endothelial Progenitor Cells to Functional Recovery After Myocardial Infarction Circulation, November 21, 2006; 114(21): 2261 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rajasingh, E. Bord, C. Luedemann, J. Asai, H. Hamada, T. Thorne, G. Qin, D. Goukassian, Y. Zhu, D. W. Losordo, et al. IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression FASEB J, October 1, 2006; 20(12): 2112 - 2114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Qin, R. Kishore, C. M. Dolan, M. Silver, A. Wecker, C. N. Luedemann, T. Thorne, A. Hanley, C. Curry, L. Heyd, et al. Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF PNAS, July 18, 2006; 103(29): 11015 - 11020. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Marwaha, Y.-H. Chen, E. Helms, S. Arad, H. Inoue, E. Bord, R. Kishore, R. D. Sarkissian, B. A. Gilchrest, and D. A. Goukassian T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NF{kappa}B-dependent Repression of the COX-2 Promoter J. Biol. Chem., September 16, 2005; 280(37): 32379 - 32388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Lele and D. J. Wolgemuth Distinct Regions of the Mouse Cyclin A1 Gene, Ccna1, Confer Male Germ-Cell Specific Expression and Enhancer Function Biol Reprod, October 1, 2004; 71(4): 1340 - 1347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kishore, C. Luedemann, E. Bord, D. Goukassian, and D. W. Losordo Tumor Necrosis Factor-Mediated E2F1 Suppression in Endothelial Cells: Differential Requirement of c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Signal Transduction Pathways Circ. Res., November 14, 2003; 93(10): 932 - 940. [Abstract] [Full Text] [PDF]
|
|