Regulation of CDK7-carboxyl-terminal domain kinase activity by the tumor suppressor p16(INK4A) contributes to cell cycle regulation

The eukaryotic cell cycle is regulated by cyclin-dependent kinases (CDKs). CDK4 and CDK6, which are activated by D-type cyclins during the G(1) phase of the cell cycle, are thought to be responsible for phosphorylation of the retinoblastoma gene product (pRb). The tumor suppressor p16(INK4A) inhibit s phosphorylation of pRb by CDK4 and CDK6 and can thereby block cell cycle progression at the G(1)/S boundary. Phosphorylation of the carboxyl-termina l domain (CTD) of the large subunit of RNA polymerase II by general transcr iption factor TFIIH is believed to be an important regulatory event in tran scription. TFIIH contains a CDK7 kinase subunit and phosphorylates the CTD. We have previously shown that p16(INK4A) inhibits phosphorylation of the C TD by TFIIH. Here we report that the ability of p16(INK4A) to inhibit CDK7- CTD kinase contributes to the capacity to induce cell cycle arrest. These r esults suggest that p16(INK4A) may regulate cell cycle progression by inhib iting not only CDK4-pRb kinase activity but also by modulating CDK7-CTD kin ase activity. Regulation of CDK7-CTD kinase activity by p16(INK4A) thus may represent an alternative pathway for controlling cell cycle progression.