RRC ID 4772
Author Fukazawa T, Fujiwara T, Uno F, Teraishi F, Kadowaki Y, Itoshima T, Takata Y, Kagawa S, Roth JA, Tschopp J, Tanaka N.
Title Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells.
Journal Oncogene
Abstract Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DR5-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transfer.
Volume 20(37)
Pages 5225-31
Published 2001-8-23
DOI 10.1038/sj.onc.1204673
PMID 11526513
MeSH Adenoviridae / genetics Apoptosis* CASP8 and FADD-Like Apoptosis Regulating Protein Carrier Proteins / metabolism Cell Division Cysteine Endopeptidases / metabolism* Down-Regulation Gene Transfer Techniques Humans Intracellular Signaling Peptides and Proteins* Multienzyme Complexes / metabolism* Mutagenesis, Site-Directed Proteasome Endopeptidase Complex Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor / metabolism* Time Factors Tumor Cells, Cultured Tumor Suppressor Protein p53 / metabolism* Ubiquitins / metabolism*
IF 7.971
Times Cited 114
DNA material AxCANCre (RDB01748)