A regulatory loop composed of RAP80-HDM2-p53 provides RAP80-enhanced p53 degradation by HDM2 in response to DNA damage.
The ubiquitin interaction motif-containing protein RAP80 plays a key role in DNA damage response signaling. Using genomic and functional analysis, we established that the expression of the RAP80 gene is regulated in a DNA damage-responsive manner by the master regulator p53. This regulation occurs at the transcriptional level through a noncanonical p53 response element in the RAP80 promoter. Although it is inducible by p53, RAP80 is also able to regulate p53 through an association with both p53 and the E3 ubiquitin ligase HDM2, providing HDM2-dependent enhancement of p53 polyubiquitination. Depletion of RAP80 by small interfering RNA stabilizes p53, which, following DNA damage, results in an increased transactivation of several p53 target genes as well as greater apoptosis. Consistent with these observations, exogenous expression of RAP80 selectively inhibits p53-dependent transactivation of target genes in an mdm2-dependent manner in MEF cells. Thus, we identify a new DNA damage-associated role for RAP80. It can function in an autoregulatory loop consisting of RAP80, HDM2, and the p53 master regulatory network, implying an important role for this loop in genome stability and oncogenesis.
Cell Biology Section, Laboratory of Respiratory Biology, Chromosome Stability Group, Laboratory of Molecular Genetics, Division of Intramural Research, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Jun
J
Yan
Daniel
D
Menendez
Xiao-Ping
XP
Yang
Michael A
MA
Resnick
Anton M
AM
Jetten
D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C466234:UIMC1 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2