GAM/ZFp/ZNF512B is central to a gene sensor circuitry involving cell-cycle regulators, TGF{beta} effectors, Drosha and microRNAs with opposite oncogenic potentials.
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.
Tili
Esmerina
E
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Biological Research Tower, Columbus, OH 43210, USA.
Michaille
Jean-Jacques
JJ
Liu
Chang-Gong
CG
Alder
Hansjuerg
H
Taccioli
Cristian
C
Volinia
Stefano
S
Calin
George A
GA
Croce
Carlo M
CM
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
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)