Premium
Inhibition of apoptosis via CHIP‐mediated proteasomal degradation of TAp73α
Author(s) -
Tanwar Kamia,
Pati Uttam
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.28386
Subject(s) - ubiquitin ligase , transactivation , tetratricopeptide , apoptosis , ubiquitin , microbiology and biotechnology , gene isoform , biology , chemistry , cancer research , transcription factor , biochemistry , gene
TAp73, a homologous of tumor suppressor p53, regulates apoptosis in a p53‐independent manner and its suppressive as well as stimulatory role in promoting angiogenesis has been reported. It exists in multiple isoforms which varies structurally in their N‐terminus and C‐terminus region and crucial interplay among them guides the decision of cell survival and death. As molecular chaperones control both stability and degradation of TAp73, selective regulation of p73 isoforms has implication upon developing new therapeutic for hypoxic tumor. We have discovered that under DNA damage carboxy terminus Hsp70 interacting protein (CHIP's) antiapoptotic function is displayed via its E3 ligase activity that inhibits exclusively TAp73α‐mediated apoptosis in cancer cell. The decrease in TAp73α level by CHIP as it is supported by increased ubiquitination pattern is reverted back by sh‐CHIP. Further, the transactivation of p53‐downstream apoptotic genes BAX , PUMA and PIG3 by TAp73α is also shown to be subsequently inhibited by CHIP. The tetratricopeptide TPR‐domain of CHIP in its amino‐terminus interacts with the carboxy‐terminus of TAp73α and ΔNp73α and as a result, U‐BOX domain of CHIP in the carboxy‐terminus is able to ubiquitinate TAp73α for proteasomal degradation. Due to lack of C‐terminus in TAp73β, CHIP fails to interact with and degrade it. In conclusion, we have thus uncovered for the first time a novel mechanism of chaperone‐assisted regulation of p73 stability as well as its apoptotic functions by CHIP that might be utilized to develop new anticancer strategies.