Control of Cell Cycle Exit and Entry by Protein Kinase B-Regulated Forkhead Transcription Factors

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

“…In rodent beta cells, FOXO1 controls various cellular responses including proliferation [4,[26][27][28][29]. Our ex vivo analyses demonstrated a progressive decrease in the localisation of nFOXO1 within proliferating cells, suggesting that FOXO1 may be involved in regulating cell cycle progression in the human fetal pancreas after 12 weeks of a c fetal age.…”

“…The majority of studies have demonstrated that FOXO1 inhibits cell proliferation at multiple phases of the cell cycle in various cells and tissues [3,[25][26][27][28][29]. To determine if there is a role for FOXO1 in cell proliferation during human fetal pancreas development, co-localisation of nFOXO1 with Ki67 was assessed (Fig.…”

Many forks in the path: cycling with FoxO

“…Consistent with this finding, The functional consequence of FoxO-mediated disruption of cyclin-CDK complex formation is to decrease the phosphorylation of the pRB family proteins, and hence E2F transcriptional activity. However, FoxO may also directly target the pRB family members p107 and p130 (also called pRB2) (Bandara et al, 1994;Giacinti and Giordano, 2006;Macaluso et al, 2006); mammalian FoxO3a and FoxO4 have been shown to directly activate the transcription of the p130 gene, which can induce cells to undergo cell cycle arrest and enter a quiescent state (Kops et al, 2002b). Interestingly, some cell cycle regulators, including p107, pRB, E2F1-3, cyclin D1, cyclin E1/2, cyclin A1/2, CDK2 and CDC2 are themselves transcriptional targets of E2F-and pRBrelated proteins (Dalton, 1992;Furukawa et al, 1994;Shan et al, 1994;Ohtani et al, 1995;Schulze et al, 1995;Sears et al, 1997;Araki et al, 2003;Cobrinik, 2005).…”

“…The PI3K-PKB signalling cascade is a key pathway by which cells may respond to a wide range of stimuli, which may be generated intrinsically (for example, growth factors, cytokines and cell-cell contact) or from an external source (for example, irradiation, and physical or genotoxic stress) (Leevers et al, 1999;Hennessy et al, 2005;Wymann and Marone, 2005;Samuels and Ericson, 2006). At the molecular level, many of the PI3K-PKB-mediated mitogenic responses are achieved through the direct repression of FoxO transcription factors by PKB-mediated phosphorylation, promoting nuclear export, proteosomal degradation and a decrease in transactivation activity (Brunet et al, 1999(Brunet et al, , 2001Kops et al, 2002b;Jacobs et al, 2003). FoxO is also a target of many other kinases, including serum and glucocorticoid-regulated kinase, c-Jun N-terminal kinase, a dual specificity tyrosinephosphorylated and regulated kinase (DYRK1A), CDK2 and IkB kinase (Brunet et al, 1999(Brunet et al, , 2001Kops et al, 2002b;Jacobs et al, 2003;Greer and Brunet, 2005) and the deregulation of PKB and these kinases is frequently observed in proliferative disorders and can contribute significantly to tumorigenesis (Hennessy et al, 2005;Samuels and Ericson, 2006).…”

“…At the molecular level, many of the PI3K-PKB-mediated mitogenic responses are achieved through the direct repression of FoxO transcription factors by PKB-mediated phosphorylation, promoting nuclear export, proteosomal degradation and a decrease in transactivation activity (Brunet et al, 1999(Brunet et al, , 2001Kops et al, 2002b;Jacobs et al, 2003). FoxO is also a target of many other kinases, including serum and glucocorticoid-regulated kinase, c-Jun N-terminal kinase, a dual specificity tyrosinephosphorylated and regulated kinase (DYRK1A), CDK2 and IkB kinase (Brunet et al, 1999(Brunet et al, , 2001Kops et al, 2002b;Jacobs et al, 2003;Greer and Brunet, 2005) and the deregulation of PKB and these kinases is frequently observed in proliferative disorders and can contribute significantly to tumorigenesis (Hennessy et al, 2005;Samuels and Ericson, 2006). The intimate link between FoxO signalling and regulation of cell cycle control is highlighted by the fact that in these instances the re-introduction of FoxO expression, for example in PTEN-deficient tumours, can induce cell cycle arrest followed by cell death (Nakamura et al, 2000).…”