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Tumor suppressor protein (p)53, is a regulator of NF-kappaB repression by the glucocorticoid receptor.


ABSTRACT: Glucocorticoids can inhibit inflammation by abrogating the activity of NF-?B, a family of transcription factors that regulates the production of proinflammatory cytokines. To understand the molecular mechanism of repression of NF-?B activity by glucocorticoids, we performed a high-throughput siRNA oligo screen to identify novel genes involved in this process. Here, we report that loss of p53, a tumor suppressor protein, impaired repression of NF-?B target gene transcription by glucocorticoids. Additionally, loss of p53 also impaired transcription of glucocorticoid receptor (GR) target genes, whereas upstream NF-?B and glucocorticoid receptor signaling cascades remained intact. We further demonstrate that p53 loss severely impaired glucocorticoid rescue of death in a mouse model of LPS shock. Our findings unveil a new role for p53 in the repression of NF-?B by glucocorticoids and suggest important implications for treatment of the proinflammatory microenvironments found in tumors with aberrant p53 activity.

SUBMITTER: Murphy SH 

PROVIDER: S-EPMC3193198 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Tumor suppressor protein (p)53, is a regulator of NF-kappaB repression by the glucocorticoid receptor.

Murphy Samantha H SH   Suzuki Kotaro K   Downes Michael M   Welch Genevieve L GL   De Jesus Paul P   Miraglia Loren J LJ   Orth Anthony P AP   Chanda Sumit K SK   Evans Ronald M RM   Verma Inder M IM  

Proceedings of the National Academy of Sciences of the United States of America 20110926 41


Glucocorticoids can inhibit inflammation by abrogating the activity of NF-κB, a family of transcription factors that regulates the production of proinflammatory cytokines. To understand the molecular mechanism of repression of NF-κB activity by glucocorticoids, we performed a high-throughput siRNA oligo screen to identify novel genes involved in this process. Here, we report that loss of p53, a tumor suppressor protein, impaired repression of NF-κB target gene transcription by glucocorticoids. A  ...[more]

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