Relief of p53-mediated telomerase suppression by p73.
Reactivation of telomerase is a feature in many cancer cells. Telomerase activation inhibits telomere shortening, thereby preventing cell cycle arrest and apoptosis activated by shortened telomeres or chromosomal rearrangements. The tumor-suppressor gene product, p53, was previously shown to transcriptionally suppress the activation of the catalytic subunit of telomerase (hTERT). Here we have evaluated the role of p73 in hTERT regulation. We found that ectoptic expression of p73beta, in contrast to p73alpha or p53, in p53 null H1299 cells does not lead to suppression of hTERT transcription. However co-expression of p73alpha or p73beta together with p53 abolished p53-mediated hTERT suppression. This phenomenon was found to be dependent on the DNA binding ability of p73. We also show that p53-mediated suppression of hTERT transcription requires a minimum threshold level of p53, and p73 abrogates p53-mediated suppression by reducing p53 levels through the activation of HDM2. Moreover, p53-mediated hTERT suppression was not relieved by p73beta in cells depleted of HDM2 through small interfering RNA-mediated gene silencing. In addition, knockdown of HDM2 in MCF7 cells, which express moderately high levels of p73 and p53, resulted in the reduction of endogenous hTERT levels. Finally, knockdown of p73 in MCF7 cells resulted in increased p53 protein levels and a concomitant decrease in hTERT levels. Together, our data indicate a plausible way by which p73, through HDM2, can oppose p53 tumor suppressor function, thereby possibly contributing to tumorigenesis.
Toh
Wen Hong
WH
Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, National Cancer Centre, 11, Hospital Drive, Singapore 169610, Singapore.
Kyo
Satoru
S
Sabapathy
Kanaga
K
D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012313:RNA; D004247:DNA; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019098:Telomerase