HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/H1575    most recent 00364.2005v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Chen, J. Articles by Goligorsky, M. S. Search for Related Content PubMed PubMed Citation Articles by Chen, J. Articles by Goligorsky, M. S.

Contribution of p16^INK4a and p21^CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53

¹Departments of Medicine, Pharmacology, and Pathology and ²Brander Cancer Research Institute, New York Medical College, Valhalla, New York

Submitted 14 April 2005 ; accepted in final form 6 October 2005

We have previously found that nonenzymatically glycated collagen I (GC), mimicking diabetic microenvironment, can induce senescent phenotype in early passage human umbilical vein endothelial cells (HUVECs). In the present study, we explored the functional involvement of cell cycle checkpoint pathways in initiating GC-induced premature endothelial cell senescence. When compared with native collagen, early passage HUVECs showed increased p53, p21^CIP1 (p21), and p16^INK4a (p16) mRNA expression after exposure to GC. Twenty-four hours after transfection of p16, p21, and p53-enhanced green fluorescent protein (EGFP) recombinant plasmids, HUVECs entered G₁-phase cell cycle arrest. By days 3 and 5, HUVECs transfected with p16-EGFP showed an increased proportion of senescent cells, and this increase was more prominent in the GFP-positive cell population, which exhibited 68% of senescent cells. Transfection of p21 also induced senescence but only by day 5. Cotransfection of p16 and p21 showed no additive effect. Transfection of p21 or p53 induced apoptosis in HUVECs. Next, we suppressed endogenous p53, p21, p16, or retinoblastoma (Rb) gene expression through small interference RNA strategy and investigated their influence in p16- and p21-initiated endothelial cell senescence. Analysis indicated that suppression of p53 expression can abolish senescence induced by p16 overexpression. Paradoxically, this effect was not observed when p21 was suppressed. On the other hand, suppression of Rb eliminated senescence initiated by either p16 or p21 overexpression. In summary, the p53/p21 pathway is mainly responsible for GC-induced apoptosis, but the coordinated activation of the p53/p21 and p16 pathway is responsible for GC-induced endothelial cell senescence through a Rb-dependent mechanism.

cell cycle; advanced glycation end-products; apoptosis; retinoblastoma

This article has been cited by other articles:

				V. A. Luyckx, C. A. Compston, T. Simmen, and T. F. Mueller Accelerated senescence in kidneys of low-birth-weight rats after catch-up growth Am J Physiol Renal Physiol, December 1, 2009; 297(6): F1697 - F1705. [Abstract] [Full Text] [PDF]

				Y. Zhang, B.-S. Herbert, G. Rajashekhar, D. A. Ingram, M. C. Yoder, M. Clauss, and J. Rehman Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factor-{alpha} via the p38 mitogen-activated protein kinase pathway FASEB J, May 1, 2009; 23(5): 1358 - 1365. [Abstract] [Full Text] [PDF]

				J. D. Erusalimsky Vascular endothelial senescence: from mechanisms to pathophysiology J Appl Physiol, January 1, 2009; 106(1): 326 - 332. [Abstract] [Full Text] [PDF]

				P. J. Talmud, J. A. Cooper, J. Palmen, R. Lovering, F. Drenos, A. D. Hingorani, and S. E. Humphries Chromosome 9p21.3 Coronary Heart Disease Locus Genotype and Prospective Risk of CHD in Healthy Middle-Aged Men Clin. Chem., March 1, 2008; 54(3): 467 - 474. [Abstract] [Full Text] [PDF]

				S. Patschan, J. Chen, O. Gealekman, K. Krupincza, M. Wang, L. Shu, J. A. Shayman, and M. S. Goligorsky Mapping mechanisms and charting the time course of premature cell senescence and apoptosis: lysosomal dysfunction and ganglioside accumulation in endothelial cells Am J Physiol Renal Physiol, January 1, 2008; 294(1): F100 - F109. [Abstract] [Full Text] [PDF]