Phase specific functions of the transcription factor TFII-I during cell cycle

Abstract

The post-embryonic cells, in a non-proliferating quiescent state (G0), require mitogenic signaling to drive them into cell cycle entry (G1). However, cell cycle events become largely independent of external signaling once cells begin DNA synthesis in S-phase. Given these two phases of cell cycle are mechanistically distinct, it is unclear whether there could be coordinated transcriptional regulation between these phases. The signal induced multifunctional transcription factor TFII-I, upon growth factor signaling, undergoes tyrosine phosphorylation, which is essential for its transcriptional activation function and corresponding G0-G1 transition. Here we show that silencing of TFII-I has unexpected defects in S-phase. The TFII-I KD cells exhibit significant delay entering into and executing S-phase progression and entry into G2/M phase but do not exhibit any significant mitotic defects as evidenced by post-mitotic G1 entry and frequency of binucleation. Microarray analysis, coupled with functional validation, reveals cyclin D1 and PKC-β as major downstream targets of TFII-I. Cyclin D1 is induced in G1 and is necessary for G1/S transition. PKC-β also activates cyclin D1 via NFκB. These observations suggest a transcriptional network during early phases of cell cycle mediated by TFII-I. Finally, we show that Cdk1 phosphorylates TFII-I at the G2/M boundary, which likely leads to its displacement from the condensed chromatin during prophase to pro-metaphase transition. Taken together, TFII-I appears to have distinct roles in distinct phases of the mammalian cell cycle.