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

Abstract

The CCAAT/enhancer-binding protein (C/EBP) family of transcription factors plays an important role in controlling cell proliferation and differentiation. C/EBPα 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/EBPα suppresses tumorigenesis in myeloid cells and possibly other tissues. In addition, recent work has identified C/EBPα 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/EBPα 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/EBPα 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.

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

“…C/EBPb À/À mice also display elevated levels of DMBA-induced apoptosis suggesting that C/EBPb has a role in keratinocyte survival in response to oncogenic Ras signaling and/or DNA damage (Zhu et al, 2002;Johnson, 2005). These data demonstrate an important role for C/EBPb in keratinocytes survival and skin tumorigenesis.…”

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

“…C/EBPalpha and C/EBPbeta are members of the family of six functionally and structurally related basic leucine zipper DNA binding proteins. The genes regulated by the C/EBP proteins are diverse and are involved in a variety of different cell processes including hematopoiesis, adipogenesis and morphogenesis (Johnson, 2005).…”

Proliferation and cornification during development of the mammalian epidermis

“…For example, C/EBP␣ is induced in terminally differentiating adipocytes and myeloid cells, where it activates differentiation-specific genes. In addition, it is a powerful regulator of cell cycle exit (reviewed in Johnson, 2005).…”

“…Yet it seems quite likely that under stress or disease conditions, the loss of a single family member may manifest itself in the skin. For example, C/EBP␣ is strongly antiproliferative and now appears to be part of the p53-regulated growth arrest elicited by DNA damage after UV light treatment in epidermal keratinocytes (Johnson, 2005). CHOP/gadd153, a C/EBP factor that is strongly induced by UV damage in the skin (Anand et al, 2005), is known to participate in the regulation of keratinocyte apoptosis after cellular damage and ER stress (Maytin et al, 2001).…”