FOXO transcription factors at the interface between longevity and tumor suppression

Abstract

A wide range of human diseases, including cancer, has a striking age-dependent onset. However, the molecular mechanisms that connect aging and cancer are just beginning to be unraveled. FOXO transcription factors are promising candidates to serve as molecular links between longevity and tumor suppression. These factors are major substrates of the protein kinase Akt. In the presence of insulin and growth factors, FOXO proteins are relocalized from the nucleus to the cytoplasm and degraded via the ubiquitin-proteasome pathway. In the absence of growth factors, FOXO proteins translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest, stress resistance, or apoptosis. Stress stimuli also trigger the relocalization of FOXO factors into the nucleus, thus allowing an adaptive response to stress stimuli. Consistent with the notion that stress resistance is highly coupled with lifespan extension, activation of FOXO transcription factors in worms and flies increases longevity. Emerging evidence also suggests that FOXO factors play a tumor suppressor role in a variety of cancers. Thus, FOXO proteins translate environmental stimuli into changes in gene expression programs that may coordinate organismal longevity and tumor suppression.

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

“…The finding that a specific PTM is sufficient to induce a FOXO3 apoptosis program is one of the first demonstrations of a transcriptionally selective form of FOXO3 and opens the possibility that modifying this phosphorylation process in both positive and negative ways could be an important therapeutic approach. FOXO3-dependent apoptosis has been postulated to play a role in its ability to serve as a tumor suppressor, 33 has been implicated in muscle atrophy and cardiomyopathy 34 and appears to play a role in response of cancers to cytotoxic chemotherapy agents. 35 Further work will be necessary to understand the factors that regulate the ability of JNK to induce phosphorylation at this site, whether other kinases perform this function as well and whether other factors ultimately determine cell fate in the presence of p-574-FOXO3.…”

Epigenetic regulation of aging stem cells

“…All FOXO isoforms (FOXO1, FOXO3, FOXO4 and FOXO6) respond to insulin/growth factor signaling and stress stimuli to coordinate various cell responses, including proliferation, cell cycle arrest, resistance to oxidative stress, cellular metabolism and differentiation (Greer and Brunet, 2005). In invertebrates, FOXO transcription factors are important for longevity downstream of insulin signaling (Lin et al, 1997;Ogg et al, 1997;Giannakou et al, 2004;Hwangbo et al, 2004).…”

p51/p63 inhibits ultraviolet B-induced apoptosis via Akt activation

“…In contrast to keratinocytes, p51 overexpression did not block UV-B-induced apoptosis in similar experiments conducted in P19 cells, despite the observation that wortmannin enhanced apoptosis in these cells to the same extent as in keratinocytes (Figure 4f). We further examined the effects of p51 expression on the phosphoryation of FoxO1, a well-known target protein of Akt kinase (Greer and Brunet, 2005). Overexpression of TAp51B and DNp51B induced phosphorylation of FoxO1 strongly and moderately, respectively (Figure 4g).…”