Stressful signals are transduced through various signalling pathways, ultimately resulting in the altered expression of critical genes, including cycle regulatory genes. While transcriptional events regulating gene expression has been thoroughly studied, it is becoming increasingly clear that post-transcriptional regulatory mechanisms also play a critical role in gene regulation by stress. These post- transcriptional processes, still poorly understood, include mRNA processing, transport, stability and translation, as well as post- translational events such 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. Expression of various cyclins throughout the cell division cycle and in response to stress agents is likewise regulated through alterations in the half-life of their respective mRNA. Much effort is focused on searching for RNA regions and proteins involved in regulating the stability of p21, cyclins and other cell cycle regulatory genes. This analysis involves both in vitro and in vivo determinations of RNA binding and RNA degradation, the identification of the RNA-binding proteins involved and the signalling pathways that modulate their activity. We are also studying the function of the tumor suppressor gene von Hippel-Lindau (VHL) as it is believed to modulate gene expression at the levels of transcription elongation, mRNA stability and protein degradation. We are examining the function of the VHL tumor suppressor gene within the stress response. - cyclins, p21, mRNA stability, mRNA-binding proteins, apoptosis, growth arrest, VHL

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000511-02
Application #
6288714
Study Section
Special Emphasis Panel (LBC)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Institute on 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
Lecona, Emilio; Olmo, Nieves; Turnay, Javier et al. (2008) Kinetic analysis of butyrate transport in human colon adenocarcinoma cells reveals two different carrier-mediated mechanisms. Biochem J 409:311-20
Lal, Ashish; Kim, Hyeon Ho; Abdelmohsen, Kotb et al. (2008) p16(INK4a) translation suppressed by miR-24. PLoS ONE 3:e1864
Galban, Stefanie; Kuwano, Yuki; Pullmann Jr, Rudolf et al. (2008) RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha. Mol Cell Biol 28:93-107
Kim, Hyeon Ho; Abdelmohsen, Kotb; Lal, Ashish et al. (2008) Nuclear HuR accumulation through phosphorylation by Cdk1. Genes Dev 22:1804-15

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