Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors

The CCAAT/enhancer-binding protein (C/EBP) family of transcription factors plays an important role in controlling cell proliferation and differentiation. C/EBP alpha is a particularly potent regulator of cell-cycle exit and is induced in terminally differentiating adipocytes and myeloid cells, where it also activates differentiation-specific genes. The growth-inhibiting activity of C/EBP alpha suppresses tumorigenesis in myeloid cells and possibly other tissues. In addition, recent work has identified C/EBP alpha as a component of the p53-regulated growth arrest response elicited by DNA damage in epidermal keratinocytes. Several studies have explored the mechanism by which C/EBP alpha blocks cell-cycle progression at the G1-S boundary, and several models have been proposed but no universally accepted mechanism has emerged. Controversial issues include whether C/EBP alpha acts through an 'off-DNA' mechanism to inhibit cyclin-dependent kinases, and whether and how it functions with the RB-E2F system to repress transcription of S-phase genes. Other C/EBP-family members have also been implicated in positive and negative control of cell proliferation, and the mechanisms underlying their growth-regulatory activities are beginning to be elucidated.