Xiao H, Palhan V, Yang Y, Roeder R G
Laboratory of Biochemistry, The Rockefeller University, New York, NY 10021, USA.
EMBO J. 2000 Mar 1;19(5):956-63. doi: 10.1093/emboj/19.5.956.
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.
CC3是一种转移抑制因子，它通过使细胞易于凋亡来抑制变异型小细胞肺癌（v-SCLC）的转移。同一蛋白也曾被报道为细胞辅因子TIP30，它通过与Tat和RNA聚合酶II相互作用来刺激HIV-1 Tat激活的转录。我们在此报道TIP30/CC3是一种新型丝氨酸/苏氨酸激酶。它以Tat依赖的方式磷酸化最大RNA聚合酶II亚基C端结构域（CTD）的七肽重复序列。在假定的ATP结合基序中的氨基酸替换消除了TIP30激酶活性，同时也抑制了TIP30增强Tat激活转录或使NIH 3T3和v-SCLC细胞对凋亡敏感的能力。此外，v-SCLC细胞中TIP30/CC3的异位表达诱导了许多基因的表达，这些基因包括凋亡相关基因Bad和Siva，以及转移抑制因子NM23-H2。这些数据证明了TIP30/CC3功能的分子机制，并提示了一种调节凋亡的新途径。
