Transcription factors LSF and E2Fs: Tandem cyclists driving G0 to S?

Abstract

Cell cycle progression in mammalian cells from G1 into S phase requires sensing and integration of multiple inputs, in order to determine whether to continue to cellular DNA replication and subsequently, to cell division.  Passage to S requires transition through the restriction point, which at a molecular level consists of a bistable switch involving E2Fs and pRb family members.  At the G1/S boundary, a number of genes essential for DNA replication and cell cycle progression are upregulated, promoting entry into S phase.  Although the activating E2Fs are the most extensively characterized transcription factors driving G1/S expression, LSF is also a transcription factor essential for stimulating G1/S gene expression.  A critical LSF target gene at this stage, Tyms, encodes thymidylate synthetase.  In investigating how LSF is activated in a cell cycle-dependent manner, we recently identified a novel time delay mechanism for regulating its activity during G1 progression, which is apparently independent of the E2F/pRb axis.  This involves inhibition of LSF in early G1 by two major proliferative signaling pathways: ERK and cyclin C/CDK, followed by gradual dephosphorylation during mid- to late-G1.  Whether LSF and E2F act independently or in concert to promote G1/S progression remains to be determined.