Isg15 controls p53 stability and functions.
Degradation of p53 is a cornerstone in the control of its functions as a tumor suppressor. This process is attributed to ubiquitin-dependent modification of p53. In addition to polyubiquitination, we found that p53 is targeted for degradation through ISGylation. Isg15, a ubiquitin-like protein, covalently modifies p53 at 2 sites in the N and C terminus, and ISGylated p53 can be degraded by the 20S proteasome. ISGylation primarily targets a misfolded, dominant-negative p53, and Isg15 deletion in normal cells results in suppression of p53 activity and functions. We propose that Isg15-dependent degradation of p53 represents an alternative mechanism of controlling p53 protein levels, and, thus, it is an attractive pathway for drug discovery.
Institute of Molecular and Cell Biology; A*STAR; Singapore.
Yi-Fu
YF
Huang
Institute of Molecular and Cell Biology; A*STAR; Singapore.
Sheena
S
Wee
Institute of Molecular and Cell Biology; A*STAR; Singapore.
Jayantha
J
Gunaratne
p53 Laboratory; A*STAR; Singapore.
David P
DP
Lane
Institute of Molecular and Cell Biology; A*STAR; Singapore; Institute for Research on Cancer and Ageing of Nice (IRCAN); INSERM; U1081-UMR CNRS 7284; University of Nice - Sophia Antipolis; Centre Antoine Lacassagne; Nice, France.
Dmitry V
DV
Bulavin
D000818:Animals; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014452:Ubiquitins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; C489550:G1p2 protein, mouse; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C074034:ISG15 protein, human; D046988:Proteasome Endopeptidase Complex
Isg15; apoptosis; p53; protein degradation misfolded protein