Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells
Details
Serval ID
serval:BIB_2AA3E11868A9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells
Journal
Oncogene
ISSN
0950-9232 (Print)
Publication state
Published
Issued date
08/2001
Volume
20
Number
37
Pages
5225-31
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Aug 23
Research Support, Non-U.S. Gov't --- Old month value: Aug 23
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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:18
Last modification date
20/08/2019 13:10