Our major goal is to understand how the levels of mRNAs encoding cytokines and oncoproteins are regulated, because sustained synthesis of these gene products can favor cell growth rather than differentiation, a hallmark of the neoplastic phenotype. Many cytokine and proto-oncogene mRNAs exhibit extremely short half-lives which limits their use as templates for translation. Moreover, the half-lives of their mRNAs are frequently subject to regulatory control. Their decay is controlled in part by A+U-rich elements (AREs) located in the 3'-UTR. AREs target mRNAs for rapid degradation usually via a sequential, 3'-to-5' pathway involving rapid removal of the poly(A) tract followed by degradation of the mRNA body. Candidate 3'-5' activities include a deadenylase, such as PARN; the exosome, which is a large complex of exoribonucleases; and the proteasome, which appears to possess an ARE-specific ribonuclease activity. We are interested in why and how AREs target mRNAs for rapid degradation and what factors are involved in this process. Toward these ends, we utilized a previously described cell-free mRNA decay system, which reconstitutes cellular decay processes, to biochemically dissect the degradation machinery. We identified and purified the ARE-binding factor AUF1 from K562 cells, a human chronic myeloid leukemia cell line Ectopic expression of AUF1 reverses the inactivation of ARE-directed mRNA decay in hemin-treated K562 cells, supporting an in vivo role for AUF1 in mRNA destabilization. In cells AUF1 exists in complexes with other cellular proteins, such as the translation initiation factor eIF4G, the hspfhsc7O heat shock proteins, and poly(A)binding protein. AUF1 is also ubiquitinated. Under the stress of cell culture at elevated temperatures, heat shock proteins like hsp7O may prevent AUF1 from recruiting the mRNP to both the ubiquitin-proteasome pathway and ribonucleolytic degradation activities resulting in stabilization of ARE-mRNAs. Thus, our central hypothesis is that binding of AUF1 to an ARE promotes the assembly of an mRNA-protein complex that recruits the proteasome and ribonucleolytic activities to the mRNA for its destruction. We plan to utilize our cell-free mRNA decay system along with the reagents and expertise gained from our studies of AUF1 so far to further test, validate, refine, and if necessary, modify our central hypothesis of AUF1 function.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Physiological Chemistry Study Section (PC)
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Ogunbiyi, Peter
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University of Medicine & Dentistry of NJ
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Lin, Hsin-Ching; Simon, Peter J; Ysla, Riza M et al. (2017) RNA stability regulates human T cell leukemia virus type 1 gene expression in chronically-infected CD4 T cells. Virology 508:7-17
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