title: RNase L attenuates mitogen-stimulated gene expression via transcriptional and post-transcriptional mechanisms to limit the proliferative response.
abstract: The cellular response to mitogens is tightly regulated via transcriptional and post-transcriptional mechanisms to rapidly induce genes that promote proliferation and efficiently attenuate their expression to prevent malignant growth. RNase L is an endoribonuclease that mediates diverse antiproliferative activities, and tristetraprolin (TTP) is a mitogen-induced RNA-binding protein that directs the decay of proliferation-stimulatory mRNAs. In light of their roles as endogenous proliferative constraints, we examined the mechanisms and functional interactions of RNase L and TTP to attenuate a mitogenic response. Mitogen stimulation of RNase L-deficient cells significantly increased TTP transcription and the induction of other mitogen-induced mRNAs. This regulation corresponded with elevated expression of serum-response factor (SRF), a master regulator of mitogen-induced transcription. RNase L destabilized the SRF transcript and formed a complex with SRF mRNA in cells providing a mechanism by which RNase L down-regulates SRF-induced genes. TTP and RNase L proteins interacted in cells suggesting that RNase L is directed to cleave TTP-bound RNAs as a mechanism of substrate specificity. Consistent with their concerted function in RNA turnover, the absence of either RNase L or TTP stabilized SRF mRNA, and a subset of established TTP targets was also regulated by RNase L. RNase L deficiency enhanced mitogen-induced proliferation demonstrating its functional role in limiting the mitogenic response. Our findings support a model of feedback regulation in which RNase L and TTP target SRF mRNA and SRF-induced transcripts. Accordingly, meta-analysis revealed an enrichment of RNase L and TTP targets among SRF-regulated genes suggesting that the RNase L/TTP axis represents a viable target to inhibit SRF-driven proliferation in neoplastic diseases.
authors.affiliation: From the Marlene and Stewart Greenebaum Cancer Center, Departments of Microbiology and Immunology and.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Brennan-Laun
authors.affiliation: the Genetics Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Li
authors.affiliation: From the Marlene and Stewart Greenebaum Cancer Center, Departments of Microbiology and Immunology and the Research Services, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201, and.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ezelle
authors.affiliation: Departments of Microbiology and Immunology and.
authors.forename: Thiagarajan
authors.initials: T
authors.lastname: Venkataraman
authors.affiliation: the Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.affiliation: From the Marlene and Stewart Greenebaum Cancer Center, Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Wilson
authors.affiliation: From the Marlene and Stewart Greenebaum Cancer Center, Departments of Microbiology and Immunology and the Research Services, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201, and bhassel@som.umaryland.edu.
authors.forename: Bret A
authors.initials: BA
authors.lastname: Hassel
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D004722:Endoribonucleases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D008954:Models, Biological; D020871:RNA Stability / Q000187:drug effects* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D051816:Tristetraprolin / Q000378:metabolism
chemical_list: D008934:Mitogens; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease
keywords: Endoribonuclease; Mitogenic Stimuli; Post-transcriptional Regulation; RNA-binding Protein; RNase L; Serum-response Factor; Transcription Regulation; Transcriptional Regulation; Tristetraprolin; mRNA Decay