title: GAM/ZFp/ZNF512B is central to a gene sensor circuitry involving cell-cycle regulators, TGF{beta} effectors, Drosha and microRNAs with opposite oncogenic potentials.
abstract: MicroRNAs (miRNAs) are small regulatory RNAs targeting multiple effectors of cell homeostasis and development, whose malfunctions are associated with major pathologies such as cancer. Herein we show that GAM/ZFp/ZNF512B works within an intricate gene regulatory network involving cell-cycle regulators, TGFβ effectors and oncogenic miRNAs of the miR-17-92 cluster. Thus, GAM impairs the transcriptional activation of the miR-17-92 promoter by c-Myc, downregulates miR-17-92 miRNAs differentially, and limits the activation of genes responsive to TGFβ canonical pathway. In contrast, TGFβ decreases GAM transcripts levels while differentially upregulating miR-17-92 miRNAs. In turn, miR-17, miR-20a and miR-92a-1 target GAM transcripts, thus establishing a feedback autoregulatory loop. GAM transcripts are also targeted by miRNAs of the let-7 family. GAM downregulates Drosha, the main effector of miRNA maturation in the nucleus, and interacts with it in a RNA-dependent manner. Finally, GAM modulates the levels of E2F1 and Ras, and increases apoptosis while reducing cell proliferation. We propose that GAM represents a new kind of vertebrate regulator aimed at balancing the opposite effects of regulators of cell homeostasis by increasing the robustness of gene circuitries controlling cell proliferation, differentiation and development.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Biological Research Tower, Columbus, OH 43210, USA.
authors.forename: Esmerina
authors.initials: E
authors.lastname: Tili
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Michaille
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D025461:Feedback, Physiological; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D050687:E2F1 Transcription Factor; C524941:MIRN17 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; C554937:ZNF512B protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D016283:Proto-Oncogene Proteins p21(ras)