P21Waf1/Cip1 Inhibits Initiator Caspase Cleavage

Biochemical and Biophysical Research Communications 269, 179 190 (2000) doi:10.1006/bbrc.2000.2247, unattached online at http://www.idealibrary.com on p21 WAF1/CIP1 Inhibits Initiator Caspase Cleavage by liquidate back Death Receptor DR4 Shi-Qiong Xu and Wa?k S. El-Deiry 1 Laboratory of molecular(a) Oncology and Cell Cycle Regulation, Howard Hughes Medical comprise, Departments of Medicine, Genetics, Cancer magnetic core and Institute for Human Gene Therapy, University of dad School of Medicine, 437 CRB, 415 curie Boulevard, Philadelphia, Pennsylvania 19104 Received January 19, 2000 Death receptors of the Tumor Necrosis constituent (TNF) family play membrane-bound self-activating signaling complexes that initiate programmed cell death finished segmentation of proximal caspases including CASP8 and 10. Here we show that overexpression of the cytoplasmic mankind (CD) of the DR4 runway receptor (TNFRSF10A, TRAIL R1) in human breast, lung, and colon crab louse el ectric cellphoneular telephone lines, using an adenovirus vector (Ad-DR4-CD), leads to p53-independent apoptotic cell devastation involving partitioning of CASP8 and 10 proximally and CASP3, 6, and 7 distally. DR4-CD overexpression also leads to sectionalisation of poly(ADP-ribose) polymerase (PARP) and the DNA fragmentation factor (DFF45; ICAD). Importantly, normal lung ?broblasts are unsusceptible to DR4-CD overexpression and show no evidence of PARP-, CASP8- or CASP3-cleavage despite equivalent levels of adenovirus-delivered DR4-CD protein as the cancer cells. These results suggest that DR4 may signal death through know caspases and that further studies are required to appreciate Ad-DR4-CD as a refreshing anti-cancer agent. Finally, we show that overexpression of the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 (CDKN1A), or its N-terminal 91 amino acids containing cell cycle-inhibitory activity, inhibits DR4CD-dependent proximal caspase cleavage. The blockage of initi ator caspase energizing provides a novel ins! ight into how p21 may suppress apoptosis and enhance cell survival. © 2000...If you want to get a expert essay, order it on our website: BestEssayCheap.com

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