FOXO transcription factors: key regulators of cell fate

Abstract

FOXO (forkhead box O) transcription factors are crucial regulators of cell fate. This function of FOXO proteins relies on their ability to control diverse and at times, opposing cellular functions, such as proliferation, differentiation, DNA repair, defence against oxidative stress damage and apoptosis, in response to hormones, growth factors and other environmental cues. This review discusses our current understanding of the regulation and role of FOXO transcription factors in determining cell fate and highlights their relevance to tumorigenesis and drug resistance.

Many forks in the path: cycling with FoxO

“…FoxO proteins play a central role in controlling cell fate (Greer and Brunet, 2005;Lam et al, 2006). Multiple and divergent signalling pathways converge to influence FoxO activity, the net outcome of which leads to changes in the expression of genes important for cellfate determination, which is rarely observed without accompanying FoxO-induced changes in the cell cycle Figure 3 Cell-fate decisions tied to specific cell cycle phases.…”

“…Moreover, inhibition of HDACs has been reported to induce growth arrest, activation of apoptotic pathways, autophagic cell death and senescence in transformed cells (Xu et al, 2007). This raises the possibility that inhibition of sirtuin activity may also sensitize cancer cells to chemotherapeutic drugs through favouring apoptosis over stress resistance following cell cycle arrest induced by FoxO activation (Lam et al, 2006;Myatt and Lam, 2007b). In summary, the importance of FoxO proteins in cell cycle checkpoint regulation, and subsequent cell-fate determination, supports the applicability of employing FoxO regulation as a future target for therapeutic intervention in cancer.…”

Foxo in the immune system

“…Lam et al, 2006;Wijchers et al, 2006); as well as differentiation factors such as Id1 (Birkenkamp et al, 2007). Foxo proteins also protect cells from oxidative stress via the induction of target genes like superoxide dismutase (SOD) 2 (Mn-SOD) and catalase Nemoto and Finkel, 2002).…”

Toll-like receptor 9-mediated inhibition of apoptosis occurs through suppression of FoxO3a activity and induction of FLIP expression

“…The mitochondrial pathway can promote apoptosis in hematopoietic cells after activation of FoxO3a signaling (Dijkers et al, 2002). Additionally, FoxO3a mediates apoptosis by activating pro-apoptotic genes such as Fas ligand, Bim, or TNF-related apoptosis-inducing ligand (TRAIL) (Lam et al, 2006). Even though FoxO3a has generally been considered an inducer of apoptosis, there is no evidence of a relationship between FoxO3a and TLR activation.…”