The Role of The Androgen Receptor Cofactor P44/Wdr77 In Astrocyte Activation

<p>Astrogliosis is induced by neuronal damage and is also a pathological feature of the major aging-related neurodegenerative disorders. The mechanisms that control the cascade of astrogliosis have not been well established. In a previous study, we identified a novel androgen receptor (AR)-interacting protein (p44/WDR77) and found that it plays a critical role in the control of proliferation and differentiation of prostate epithelial cells. In the present study, we found that deletion of the p44 gene in the mouse brain caused accelerated aging with dramatic astrogliosis. The p44/WDR77 is expressed in astrocytes and loss of p44/WDR77 expression in astrocytes leads to astrogliosis. Our results reveal a novel role of p44/WDR77 in astrocytes, which may explain the well-documented role of androgens in suppression of astrogliosis.</p> <p>While many of detailed mechanisms of astrocyte activation remain to be elucidated, a number pathways have been implicated in astrocyte activation including p21^Cip1 and the NF-kB pathway. Astrocytic activation induced by p44/WDR77 gene deletion was associated with a significant increase of p21^Cip1 expression and NF-kB activation characterized by p65 nuclear localization. We found that down-regulation of p21^Cip1 expression inhibited astrocyte activation induced by the p44/WDR77 deletion and was accompanied by a decreased p65 nuclear localization. While p21^Cip1 role in astrocyte activation and NF-kB activation is not well understood, studies of other cell cycle regulators have implicated cell cycle control systems as modulators of astrocyte activation, thus p21^Cip1 could induce secondary effect to induce p65 nuclear localization. However, p65 knockdown completely relieved the inhibition of astrocyte growth induced by the p44/WDR77 deletion, while p21^Cip1 knockdown only partially recovered this inhibition. Thus, NF-kB activity performs additional regulatory actions not mediated by p21^Cip1. These analyses imply that p4/WDR77 suppresses astrocyte activation through modulating p21^Cip1 expressionand NF-kB activation.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• Vincent, Bryce H

Contributors dc:contributor

• Zhengxin Wang
• Gary E. Gallick
• Douglas Boyd

• p44
• NF-kappa B
• p21
• astrocytes
• androgen receptor
• astrogliosis
• Biochemistry
• Cell Biology
• Cellular and Molecular Physiology
• Laboratory and Basic Science Research
• Medical Biochemistry
• Medical Neurobiology
• Medical Sciences
• Molecular and Cellular Neuroscience
• Molecular Biology
• Neurosciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/134

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1178