In response to signals of either endogenous or exogenous origins, mammalian cells implement changes in gene expression patterns that profoundly influence the global response of the cell. While the transcriptional events regulating changes in gene expression have been thoroughly studied, post-transcriptional processes, which are less well understood, are emerging as major gene regulatory mechanisms. Post-transcriptional gene regulation includes pre-mRNA processing and maturation, mRNA transport, stability and translation, as well as protein processing, modification and degradation. With respect to mRNA stability, we are investigating the mechanisms that regulate the expression of various proliferation-associated, cell cycle regulatory, and stress-response gene products. We previously showed that the function of the RNA-binding protein HuR, which stabilizes target mRNAs, is strongly regulated by the AMP-activated kinase (AMPK). In follow-up studies, we recently found that AMPK promotes the nuclear localization of HuR by directly phosphorylating and indirectly acetylating importin a1. In separate investigations, 'en mass' analysis of HuR target transcripts using cDNA arrays recently revealed a ~20-b RNA motif present in HuR targets, which allows the successful prediction of novel HuR target transcripts. Other work has recently shown that multiple RNA-binding proteins influencing post-transcriptional fate in opposite directions (mRNA-stabilizing HuR and mRNA-destabilizing AUF1) were capable of binding target mRNAs simultaneously as well as competitively. With respect to translation, a series of systematic, cDNA-based studies have shed light on important links between enhanced mRNA stability and translational inhibition during the endoplasmic stress response.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000511-07
Application #
6969289
Study Section
(LCMB)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Anantharaman, Aparna; Gholamalamdari, Omid; Khan, Abid et al. (2017) RNA-editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA. FEBS Lett 591:2890-2904
Durie, D; Lewis, S M; Liwak, U et al. (2011) RNA-binding protein HuR mediates cytoprotection through stimulation of XIAP translation. Oncogene 30:1460-9
Wang, Peng-Yuan; Rao, Jaladanki N; Zou, Tongtong et al. (2010) Post-transcriptional regulation of MEK-1 by polyamines through the RNA-binding protein HuR modulating intestinal epithelial apoptosis. Biochem J 426:293-306
Abdelmohsen, Kotb; Gorospe, Myriam (2010) Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA 1:214-29
Costantino, Christina L; Witkiewicz, Agnieszka K; Kuwano, Yuki et al. (2009) The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res 69:4567-72
de Silanes, Isabel Lopez; Gorospe, Myriam; Taniguchi, Hiroaki et al. (2009) The RNA-binding protein HuR regulates DNA methylation through stabilization of DNMT3b mRNA. Nucleic Acids Res 37:2658-71
Hucl, Tomas; Rago, Carlo; Gallmeier, Eike et al. (2008) A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res 68:5023-30
Ishmael, Faoud T; Fang, Xi; Galdiero, Maria Rosaria et al. (2008) Role of the RNA-binding protein tristetraprolin in glucocorticoid-mediated gene regulation. J Immunol 180:8342-53
Kim, Hyeon Ho; Yang, Xiaoling; Kuwano, Yuki et al. (2008) Modification at HuR(S242) alters HuR localization and proliferative influence. Cell Cycle 7:3371-7
Kim, Hyeon Ho; Gorospe, Myriam (2008) Phosphorylated HuR shuttles in cycles. Cell Cycle 7:3124-6

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