Blockage of NF-kappaB induces serine 15 phosphorylation of mutant p53 by JNK kinase in prostate cancer cells.
The p53 tumor suppressor gene plays an important role during induction of apoptosis in cancer. In contrast, NF-kappaB prevents apoptosis in response to chemotherapeutic agents and is a critical regulator of cell survival. Despite the riches of information on the regulation of wild-type p53 function by phosphorylation, nothing is known about the modulation of mutant p53 activity by phosphorylation. Here we report that inhibition of NF-kappaB in DU145 prostate cancer cells results in p53 mutant phosphorylation at serine 15 (Ser15), leading to an increase of p53 stability, DNA binding and gain of function. Serine 15-phosphorylation is due to GADD45alpha-dependent induction of JNK kinase, which can be blocked by SP600125, a JNK kinase inhibitor. Furthermore, inhibition of GADD45alpha by small interfering RNA blocks JNK activation and abrogates Ser15 phosphorylation. Together, these results highlight the importance of Ser15 phosphorylation in regulating the oncogenic function of mutant p53 and apoptosis induction in the context of the NF-kappaB/IkappaB signaling pathway.
Zerbini
Luiz F
LF
New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA. lzerbini@bidmc.harvard.edu
Wang
Yihong
Y
Correa
Ricardo G
RG
Cho
Je-Yoel
JY
Libermann
Towia A
TA
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D047468:Immunoprecipitation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013696:Temperature; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism; D000097642:GADD45 Proteins
D000873:Anthracenes; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004247:DNA; D048670:MAP Kinase Kinase 4; D016328:NF-kappa B; D009687:Nuclear Proteins; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D012694:Serine; D016159:Tumor Suppressor Protein p53; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C432165:pyrazolanthrone