The RNA helicase p68 modulates expression and function of the Δ133 isoform(s) of p53, and is inversely associated with Δ133p53 expression in breast cancer.
The RNA helicase p68 is a potent co-activator of p53-dependent transcription in response to DNA damage. Previous independent studies have indicated that p68 and the Δ133p53 isoforms, which modulate the function of full-length p53, are aberrantly expressed in breast cancers. Here we identify a striking inverse association of p68 and Δ133p53 expression in primary breast cancers. Consistent with these findings, small interfering RNA depletion of p68 in cell lines results in a p53-dependant increase of Δ133p53 in response to DNA damage, suggesting that increased Δ133p53 expression could result from downregulation of p68 and provide a potential mechanistic explanation for our observations in breast cancer. Δ133p53α, which has been shown to negatively regulate the function of full-length p53, reciprocally inhibits the ability of p68 to stimulate p53-dependent transcription from the p21 promoter, suggesting that Δ133p53α may be competing with p68 to regulate p53 function. This hypothesis is underscored by our observations that p68 interacts with the C-terminal domain of p53, co-immunoprecipitates 133p53α from cell extracts and interacts only with p53 molecules that are able to form tetramers. These data suggest that p68, p53 and 133p53α may form part of a complex feedback mechanism to regulate the expression of Δ133p53, with consequent modification of p53-mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild-type p53.
Moore
H C
HC
Centre for Oncology & Molecular Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, Tayside, UK.
Jordan
L B
LB
Bray
S E
SE
Baker
L
L
Quinlan
P R
PR
Purdie
C A
CA
Thompson
A M
AM
Bourdon
J-C
JC
Fuller-Pace
F V
FV
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D053487:DEAD-box RNA Helicases
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