The glucose-sensing transcription factor MLX balances metabolism and stress to suppress apoptosis and maintain spermatogenesis.

Autor: Carroll PA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America., Freie BW; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America., Cheng PF; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America., Kasinathan S; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America., Gu H; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America., Hedrich T; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America., Dowdle JA; Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America., Venkataramani V; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Ramani V; Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America., Wu X; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America., Raftery D; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America., Shendure J; Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.; Howard Hughes Medical Institute, Seattle, Washington, United States of America.; Brotman Baty Institute for Precision Medicine, Seattle, Washington, United States of America., Ayer DE; Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, United States of America., Muller CH; Male Fertility Lab, Department of Urology, University of Washington, Seattle, Washington, United States of America., Eisenman RN; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2021 Oct 20; Vol. 19 (10), pp. e3001085. Date of Electronic Publication: 2021 Oct 20 (Print Publication: 2021).
DOI: 10.1371/journal.pbio.3001085
Abstrakt: Male germ cell (GC) production is a metabolically driven and apoptosis-prone process. Here, we show that the glucose-sensing transcription factor (TF) MAX-Like protein X (MLX) and its binding partner MondoA are both required for male fertility in the mouse, as well as survival of human tumor cells derived from the male germ line. Loss of Mlx results in altered metabolism as well as activation of multiple stress pathways and GC apoptosis in the testes. This is concomitant with dysregulation of the expression of male-specific GC transcripts and proteins. Our genomic and functional analyses identify loci directly bound by MLX involved in these processes, including metabolic targets, obligate components of male-specific GC development, and apoptotic effectors. These in vivo and in vitro studies implicate MLX and other members of the proximal MYC network, such as MNT, in regulation of metabolism and differentiation, as well as in suppression of intrinsic and extrinsic death signaling pathways in both spermatogenesis and male germ cell tumors (MGCTs).
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RNE is a member of the Scientific Advisory Boards of Kronos Bio Inc. and Shenogen Pharma, Beijing. There is no overlap between the research presented in this manuscript with the products or methods related to these companies.
Databáze: MEDLINE
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