TIP30 has an intrinsic kinase activity required for up-regulation of a subset of apoptotic genes.
CC3 is a metastasis suppressor that inhibits metastasis of the variant small cell lung carcinoma (v-SCLC) by predisposing cells to apoptosis. The same protein was also reported as a cellular cofactor, TIP30, which stimulates HIV-1 Tat-activated transcription by interacting with both Tat and RNA polymerase II. We report here that TIP30/CC3 is a novel serine/threonine kinase. It phosphorylates the heptapeptide repeats of the C-terminal domain (CTD) of the largest RNA polymerase II subunit in a Tat-dependent manner. Amino acid substitutions in the putative ATP binding motif that abolish the TIP30 kinase activity also inhibit the ability of TIP30 to enhance Tat-activated transcription or to sensitize NIH 3T3 and v-SCLC cells to apoptosis. Furthermore, ectopic expression of TIP30/CC3 in v-SCLC cells induces expression of a number of genes that include the apoptosis-related genes Bad and Siva, as well as metastasis suppressor NM23-H2. These data demonstrate a molecular mechanism for TIP30/CC3 function and suggest a novel pathway for regulating apoptosis.
Xiao
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Laboratory of Biochemistry, The Rockefeller University, New York, NY 10021, USA.
Palhan
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V
Yang
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Roeder
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RG
D000123:Acetyltransferases; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D016147:Genes, Tumor Suppressor; D006801:Humans; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
D014157:Transcription Factors; D000123:Acetyltransferases; C111246:HTATIP2 protein, human; D011494:Protein Kinases; D012319:RNA Polymerase II