TFII-I: Connecting Mitogenic Signals to Cell Cycle Regulation

Abstract

Reproduction, or the faithful passage of genetic information from one cell to its progeny, is central to life. To achieve reproduction faithfully cells have developed the cell cycle during which error-free replication of DNA, followed by division of the nucleus and partitioning of the cytoplasm yields two daughter cells. Prior to committing to reproduction, cells must sense mitogen levels in their environment and transduce those signals to the nucleus through a series of biochemical steps, resulting in spatial and/or temporal activation of genes that will drive cell cycle progression past the restriction point and initiate DNA replication. One way external signals are transmitted to the nucleus is via mitogen inducible transcription factors that shuttle between the cytoplasm and nucleus. Here we introduce a newly discovered pathway by which TFII-I, a growth signal induced transcription factor, operates in the prerestriction point and mitogen dependent phase of the cell cycle. We also discuss a potential role for TFII-I in DNA repair and how it might be involved in signal dependent DNA repair versus cell cycle.

Identification of the TFII-I family target genes in the vertebrate genome

“…Opn, important cytokine regulator, and Nedd8, involved in ubiquitination, were also identified as BEN-specific targets. TFII-I proteins are known to be involved in cell cycle regulation through their interaction with Rb protein (19) or regulation of cyclin D1 (20). Here, we have demonstrated that both BEN and TFII-I recruited to the promoter of Ccnd3, which supports the role of TFII-I transcription factors in the cell cycle.…”

Signal-induced functions of the transcription factor TFII-I

“…Consistent with the fact that TFII-I delivers the growth factor dependent transcriptional signal to the cyclin D1 promoter, mutation of tyrosine residues in TFII-I, which are required for its mitogen mediated transcriptional activity, abolishes cyclin D1 gene expression (61). Thus, TFII-I may provide a molecular link between mitogen-dependent signaling and nuclear gene expression to control cell division and proliferation (62).…”

“…Although ectopic expression of TFII-I results in elevated cyclin D1 levels and bypass radiation induced cell cycle block, it is undetermined whether these cells progress through cycle despite DNA damage or whether they undergo DNA repair (61,62). Moreover, it also remains to be shown whether TFII-I undergoes preferential degradation during particular phases of the cell cycle and what molecular mechanism(s) might govern this timed destruction (62).…”

“…Moreover, it also remains to be shown whether TFII-I undergoes preferential degradation during particular phases of the cell cycle and what molecular mechanism(s) might govern this timed destruction (62). Because the TFII-I protein can undergo various post-translational modifications (e.g., phosphorylation, sumoylation and ubiquitination), it is likely that some of these modifications selectively occur at particular phase of the cell cycle (62).…”

“…Moreover, it also remains to be shown whether TFII-I undergoes preferential degradation during particular phases of the cell cycle and what molecular mechanism(s) might govern this timed destruction (62). Because the TFII-I protein can undergo various post-translational modifications (e.g., phosphorylation, sumoylation and ubiquitination), it is likely that some of these modifications selectively occur at particular phase of the cell cycle (62). It is tempting to conjecture that the ability to undergo different kinds of post-translational modifications might endow TFII-I with significant plasticity, allowing it to differentially respond to a variety of signals in a cell cycle and differentiation stage specific fashion (Figure 4).…”