In response to signals of either endogenous and exogenous origin, mammalian cells activate a series of events leading to changes in gene expression and to the implementation of a global cellular response. While the transcriptional events regulating such changes in gene expression have been thoroughly studied, it is becoming increasingly clear that posttranscriptional regulatory mechanisms, which are less well understood, are also critically involved. These posttranscriptional events include mRNA processing, transport, stability and translation, as well as protein processing, phosphorylation and degradation. With respect to mRNA stability, we are investigating the mechanisms regulating the expression of various cell cycle regulatory molecules. Expression of p21, an inhibitor of cyclin-dependent kinases, is induced by various stresses (such as ultraviolet light) through stabilization of its mRNA by the RNA-binding protein HuR. Likewise, the expression of cyclins A and B1 throughout the cell division cycle is regulated through the cyclic association of their respective mRNAs with HuR, which results in transcript stabilization. Conversely, the decreased expression of cyclin D1 following treatment with the stress agent prostaglandin A2 is accomplished through cyclin D1 mRNA destabilization and is likely to involve the RNA-binding protein AUF1. Our efforts are focused on searching for RNA-binding proteins, target mRNA regions and signaling pathways involved in regulating the stability of mRNAs encoding growth control and cell cycle regulatory genes.The product of the tumor suppressor gene von Hippel-Lindau (pVHL) is believed to modulate gene expression at the levels of transcription elongation, mRNA stability and protein degradation. However, the mechanisms whereby pVHL exerts its tumor suppressive function remain to be determined. We are currently investigating pVHL's influence on gene expression by using SAGE analysis, and are seeking to identify proteins that interact with pVHL. We anticipate that these studies will help elucidate pVHL's function and its tumor suppressor properties.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000511-03
Application #
6431425
Study Section
(LBC)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2000
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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