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Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor
1George Whipple Laboratory for Cancer Research, Department of Pathology, and The Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Abstract:
Whereas several apoptosis-related proteins have been linked to the antiapoptotic effects of Akt serine-threonine kinase, the search continues to explain the Akt signaling role in promoting cell survival via antiapoptotic effects. Here, we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790. A mutation at AR Ser-210 results in the reversal of Akt-mediated suppression of AR transactivation. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway results in the suppression of AR target genes, such as p21, and the decrease of androgen/AR-mediated apoptosis, which may involve the inhibition of interaction between AR and AR coregulators. Together, these findings provide a molecular basis for cross-talk between two signaling pathways at the level of Akt and AR-AR coregulators that may help us to better understand the roles of Akt in the androgen/AR-mediated apoptosis.
Insights
Akt serine-threonine kinase phosphorylates the androgen receptor (AR), impacting AR transactivation and androgen-mediated apoptosis. This reveals a molecular link between Akt signaling and AR pathways in cell survival.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Akt serine-threonine kinase is known to promote cell survival through antiapoptotic effects.
- The precise mechanisms by which Akt influences apoptosis, particularly in relation to the androgen receptor (AR), are not fully elucidated.
- Understanding Akt's role in AR-mediated apoptosis is crucial for deciphering cell survival pathways.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the interaction between Akt signaling and the androgen receptor (AR).
- To determine if Akt directly phosphorylates the AR and how this affects AR function and apoptosis.
- To elucidate the role of Akt in regulating AR target genes and androgen/AR-mediated apoptosis.
Main Methods:
- Phosphorylation site mapping of the androgen receptor (AR) by Akt serine-threonine kinase.
- Site-directed mutagenesis of identified phosphorylation sites (Ser-210 and Ser-790) on the AR.
- Analysis of AR transactivation activity, AR target gene expression (e.g., p21), and apoptosis levels.
- Investigation of the interaction between AR and AR coregulators.
Main Results:
- Akt directly phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790.
- Mutation of AR Ser-210 reverses Akt-mediated suppression of AR transactivation.
- Activation of the phosphatidylinositol-3-OH kinase/Akt pathway suppresses AR target genes like p21 and reduces androgen/AR-mediated apoptosis.
- This reduction in apoptosis may involve inhibited interaction between AR and its coregulators.
Conclusions:
- Akt serine-threonine kinase directly phosphorylates the androgen receptor (AR), modulating its activity.
- This cross-talk between Akt and AR signaling pathways provides a molecular basis for Akt's role in promoting cell survival.
- Findings enhance understanding of Akt's function in androgen/AR-mediated apoptosis and may have implications for cancer research.