Cables1 (Cdk5 and Abl enzyme substrate 1) is a vital cell cycle regulator and a candidate tumor suppressor that negatively regulates cell growth by inhibiting cyclin-dependent kinases. Here, we report on the critical role of the Cables1/p21 pathway, which inhibits cell proliferation and induces cell senescence in human umbilical vein endothelial cells. Moreover, we confirmed that silencing of Cables1 promoted cell proliferation as well as increased resistance to angiotensin II-induced senescence, at least in part, by altering Cables1 activation. We further demonstrated that knockdown of p21 reverses Cables1-mediated cell growth inhibition and cell senescence. Taken together, these results suggest that the Cables1/p21 pathway has a strong effect on the induction of cell senescence and inhibition of cell growth, and acts as a novel regulatory mechanism in which p21 is probably one of several downstream effector molecules to mediate Cables1.

Kohn RR: Heart and cardiovascular system; in Finch CE, Hayflick L (eds): Handbook of the Biology of Aging. New York, VNR, 1977, pp 281-317.
Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE: Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994;24:471-476.
van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi T, Ullrich V, Luscher TF: Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 2000;192:1731-1744.
Lakatta EG, Levy D: Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises. Part I. Aging arteries: a “set up” for vascular disease. Circulation 2003;107:139-146.
Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, Magner M, Asahara M, Isner JM: Age-dependent impairment of angiogenesis. Circulation 1999;99:111-120.
Eggen DA, Solberg LA: Variation of atherosclerosis with age. Lab Invest 1968;18:571-579.
Strong JP, McGill HC Jr: The natural history of coronary atherosclerosis. Am J Pathol 1962;40:37-49.
Weingand KW, Clarkson TB, Adams MR, Bostrom AD: Effects of age and/or puberty on coronary artery atherosclerosis in cynomolgus monkeys. Atherosclerosis 1986;62:137-144.
Erusalimsky JD, Kurz DJ: Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp Gerontol 2005;40:634-642.
Fuster JJ, Andres V: Telomere biology and cardiovascular disease. Circ Res 2006;99:1167-1180.
Minamino T, KomuroI I: Role of telomeres in vascular senescence. Front Biosci 2008;13:2971-2979.
Yang J, Chang D, Cherry AM, Bangs CD, Oei Y, Bodnar A, Chiu CP, Herron GS: Human endothelial cell life extension by telomerase expression. J Biol Chem 1999;274:26141-26148.
Najjar SS, Scuteri A, Lakatta EG: Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005;46:54-462.
Eguchi S, Inagami T: Signal transduction of angiotensin II type 1 receptor through receptor tyrosine kinase. Regul Pept 2000;91:13-20.
Berk BC, Corson MA: Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. Circ Res 1997;80:607-616.
Wu CL, Kirley SD, Xiao H, Chuang Y, Chung DC, Zukerberg LR: Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers. Cancer Res 2001;61:7325-7332.
Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu CL, Lanier LM, Gertler FB, Vidal M, Van Etten RA, Tsai LH: Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 2000;26:633-646.
Zukerberg LR, DeBernardo RL, Kirley SD, D'Apuzzo M, Lynch MP, Littell RD, Duska LR, Boring L, Rueda BR: Loss of cables, a cyclin-dependent kinase regulatory protein, is associated with the development of endometrial hyperplasia and endometrial cancer. Cancer Res 2004;24:202-208.
Dong Q, Kirley S, Rueda B, Zhao C, Zukerberg L, Oliva E: Loss of cables, a novel gene on chromosome 18q, in ovarian cancer. Mod Pathol 2003;16:863-868.
Park DY, Sakamoto H, Kirley SD, Ogino S, Kawasaki T, Kwon E, Mino-Kenudson M, Lauwers GY, Chung DC, Rueda BR, Zukerberg LR: The Cables gene on chromosome 18q is silenced by promoter hypermethylation and allelic loss in human colorectal cancer. Am J Pathol 2007;171:1509-1519.
Tan D, Kirley S, Li Q, Ramnath N, Slocum HK, Brooks JS, Wu CL, Zukerberg LR: Loss of cables protein expression in human non-small cell lung cancer: a tissue microarray study. Hum Pathol 2003;34:143-149.
Arnason T, Pino MS, Yilmaz O, Kirley SD, Rueda BR, Chung DC, Zukerberg LR: Cables1 is a tumor suppressor gene that regulates intestinal tumor progression in Apc(Min) mice. Cancer Biol Ther 2013;14:672-678.
Tsuji K, Mizumoto K, Yamochi T, Nishimoto I, Matsuoka M: Differential effect of ik3-1/cables on p53- and p73-induced cell death. J Biol Chem 2002;277:2951-2957.
Shi Z, Li Z, Li ZJ, Cheng K, Du Y, Fu H, Khuri FR: Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3. Oncogene 2015;34:2538-2545.
Matsuoka M, Matsuura Y, Semba K, Nishimoto I: Molecular cloning of a cyclin-like protein associated with cyclin-dependent kinase 3 (cdk 3) in vivo. Biochem Biophys Res Commun 2000;273:442-447.
Komiya T, Hosono Y, Hirashima T, Masuda N, Yasumitsu T, Nakagawa K, Kikui M, Ohno A, Fukuoka M, Kawase I: p21 expression as a predictor for favorable prognosis in squamous cell carcinoma of the lung. Clin Cancer Res 1997;3:1831-1835.
Kirley SD, Rueda BR, Chung DC, Zukerberg LR: Increased growth rate, delayed senescense and decreased serum dependence characterize Cables-deficient cells. Cancer Biol Ther 2005;4:654-658.
Wang N, Guo L, Rueda BR, Tilly JL: Cables1 protects p63 from proteasomal degradation to ensure deletion of cells after genotoxic stress. EMBO Rep 2010;11:633-639.
Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T, Miyauchi H, Orimo M, Okada S, Takamura M, Nagai T, Kaneko S, Komuro I: Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation 2006;114:953-960.
Merched AJ, Chan L: Absence of p21Waf1/Cip1/Sdi1 modulates macrophage differentiation and inflammatory response and protects against atherosclerosis. Circulation 2004;110:3830-3841.
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