Transcription factor forkhead family

Rena, G., Guo, S., Cichy, S. C., Unterman, T. G., and Cohen, P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem 274 (1999)17179-17183. 

A3 receptors have been associated with the PI3K/Akt pathway (Merighi et al. 2003). Active Akt causes a variety of biological effects, including suppression of apoptosis by phosphorylation and inactivation of several targets along pro-apoptotic pathways (Vivanco and Sawyers 2002). In particular, activated Akt is able to phos-phorylate a variety of downstream substrates, for example the pro-apoptotic molecule Bad, caspase-9, the forkhead family transcription factors, I-K (a kinase that regulates the NF-kB transcription factor) and Raf. 

Once activated, Akt acts on a variety of targets and promotes cell survival by inhibiting substrates involved in the apoptotic pathway including Bad, caspases-9, members of the forkhead family of transcription factors (FOXO), and glycogen synthase kinase-3,3 (GSK-3/3) (Brazil and Hemmings, 2001). 

However, not all survival-promoting signals act via Akt. For example, cAMP-mediated neuronal survival occurs in an Akt-independent manner (Li et al., 2000). The mechanisms of Akt-induced survival are only now falling in place. Akt phosphorylates the proapoptotic Bcl-2 family member, Bad. Phosphorylation of Bad results in decreased formation of the Bad-Bcl-XL heterodimer. This allows free Bcl-xL to protect the cell from apoptosis (Cantley, 2002 Vivanco and Sawyers, 2002). Although this appears to be an important mechanism for PI-3-K-induced cell survival, alternate mechanisms might exist. Bad is expressed in RPE cells (Mukherjee et al., 2004). In certain cell types where Bad is not expressed, PI-3-K/Akt still prevents apoptosis. Possible alternate mechanisms by which PT3-K may promote cell survival are as follows (1) Akt also phosphorylates the Forkhead-related transcription factor (FKHR) in the cytoplasm. 

The mode of action of Smad 4 clearly differs from that of the other members of the Smad family. Smad 4 binds to phosphorylated R-Smads and forms trimeric complexes composed of two R-Smad molecules and one Smad 4 molecule. These complexes translocate to the nucleus, where they bind to related DNA elements and activate the transcription of target genes. The mechanism of transcription regulation by Smads is complex and includes both positive and negative influences. Generally, Smad-dependent regulation of transcription requires the interaction with other transcription factors, such as members of the FoxH 1 family of forkhead transcription factors, the Vitamin D receptor and the c-Jun transcription factor, among others (review Attisano et al., 2001). Futhermore, Smads can interact with coactivators and corepressors of transcription and thereby recruit, e. g., histone acetylase activity or histone deacetylase activity to chromatin. 

J.D. Fontenot, A.Y. Rudensky, A well adapted regulatory contrivance regulatory T cell development and the forkhead family transcription factor Foxp3, Nat. Immunol. 2005, 6, 331-337. 

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