Loss of the tumor suppressor BIN1 enables ATM Ser/Thr kinase activation by the nuclear protein E2F1 and renders cancer cells resistant to cisplatin.

Autor:	Folk WP; From the Biochemistry and Cancer Biology Graduate Program, Augusta University, Augusta, Georgia 30912.; the Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.; the Tumor Signaling and Angiogenesis Program, Georgia Cancer Center, Augusta University, Augusta, Georgia 30912., Kumari A; the Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.; the Tumor Signaling and Angiogenesis Program, Georgia Cancer Center, Augusta University, Augusta, Georgia 30912., Iwasaki T; the Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.; the Tumor Signaling and Angiogenesis Program, Georgia Cancer Center, Augusta University, Augusta, Georgia 30912.; the Division of Signal Pathways, Biosignal Research Center, Kobe University, Kobe 657, Japan., Pyndiah S; the Molecular Signaling Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112., Johnson JC; the Medicinal Chemistry and Molecular Pharmacology Graduate Program, Purdue University, West Lafayette, Indiana 47907, and., Cassimere EK; the Molecular Signaling Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.; the Medicinal Chemistry and Molecular Pharmacology Graduate Program, Purdue University, West Lafayette, Indiana 47907, and., Abdulovic-Cui AL; the Department of Biological Sciences, College of Science and Mathematics, Augusta University, Augusta, Georgia 30904., Sakamuro D; From the Biochemistry and Cancer Biology Graduate Program, Augusta University, Augusta, Georgia 30912, dsakamuro@augusta.edu.; the Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.; the Tumor Signaling and Angiogenesis Program, Georgia Cancer Center, Augusta University, Augusta, Georgia 30912.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2019 Apr 05; Vol. 294 (14), pp. 5700-5719. Date of Electronic Publication: 2019 Feb 07.
DOI:	10.1074/jbc.RA118.005699
Abstrakt:	The tumor suppressor bridging integrator 1 (BIN1) is a corepressor of the transcription factor E2F1 and inhibits cell-cycle progression. BIN1 also curbs cellular poly(ADP-ribosyl)ation (PARylation) and increases sensitivity of cancer cells to DNA-damaging therapeutic agents such as cisplatin. However, how BIN1 deficiency, a hallmark of advanced cancer cells, increases cisplatin resistance remains elusive. Here, we report that BIN1 inactivates ataxia telangiectasia-mutated (ATM) serine/threonine kinase, particularly when BIN1 binds E2F1. BIN1 + 12A (a cancer-associated BIN1 splicing variant) also inhibited cellular PARylation, but only BIN1 increased cisplatin sensitivity. BIN1 prevented E2F1 from transcriptionally activating the human ATM promoter, whereas BIN1 + 12A did not physically interact with E2F1. Conversely, BIN1 loss significantly increased E2F1-dependent formation of MRE11A/RAD50/NBS1 DNA end-binding protein complex and efficiently promoted ATM autophosphorylation. Even in the absence of dsDNA breaks (DSBs), BIN1 loss promoted ATM-dependent phosphorylation of histone H2A family member X (forming γH2AX, a DSB biomarker) and mediator of DNA damage checkpoint 1 (MDC1, a γH2AX-binding adaptor protein for DSB repair). Of note, even in the presence of transcriptionally active ( i.e. proapoptotic) TP53 tumor suppressor, BIN1 loss generally increased cisplatin resistance, which was conversely alleviated by ATM inactivation or E2F1 reduction. However, E2F2 or E2F3 depletion did not recapitulate the cisplatin sensitivity elicited by E2F1 elimination. Our study unveils an E2F1-specific signaling circuit that constitutively activates ATM and provokes cisplatin resistance in BIN1-deficient cancer cells and further reveals that γH2AX emergence may not always reflect DSBs if BIN1 is absent. (© 2019 Folk et al.)
Databáze:	MEDLINE
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