The SIAH1-HIPK2-p53ser46 Damage Response Pathway is Involved in Temozolomide-Induced Glioblastoma Cell Death

Molecular Cancer Research : MCR
Yang HeBernd Kaina

Abstract

Patients suffering from glioblastoma have a dismal prognosis, indicating the need for new therapeutic targets. Here we provide evidence that the DNA damage kinase HIPK2 and its negative regulatory E3-ubiquitin ligase SIAH1 are critical factors controlling temozolomide-induced cell death. We show that HIPK2 downregulation (HIPK2kd) significantly reduces the level of apoptosis. This was not the case in glioblastoma cells expressing the repair protein MGMT, suggesting that the primary DNA lesion responsible for triggering HIPK2-mediated apoptosis is O6 -methylguanine. Upon temozolomide treatment, p53 becomes phosphorylated whereby HIPK2kd had impact exclusively on ser46, but not ser15. Searching for the transcriptional target of p-p53ser46, we identified the death receptor FAS (CD95, APO-1) being involved. Thus, the expression of FAS was attenuated following HIPK2kd, supporting the conclusion that HIPK2 regulates temozolomide-induced apoptosis via p-p53ser46-driven FAS expression. This was substantiated in chromatin-immunoprecipitation experiments, in which p-p53ser46 binding to the Fas promotor was regulated by HIPK2. Other pro-apoptotic proteins such as PUMA, NOXA, BAX, and PTEN were not affected in HIPK2kd, and also double-stra...Continue Reading

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Citations

Mar 31, 2019·International Journal of Molecular Sciences·Yang He, Bernd Kaina
Oct 18, 2019·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Magdalena C Liebl, Thomas G Hofmann
Sep 27, 2020·International Journal of Molecular Sciences·Bernd KainaBodo Haas
Dec 17, 2020·Frontiers in Oncology·Nico ScholzJulien D F Licchesi
Feb 17, 2021·Nucleic Acids Research·Magdalena C LieblThomas G Hofmann
Jul 21, 2021·Trends in Genetics : TIG·Hartwig Visser, Adam D Thomas
May 12, 2020·Chemical Research in Toxicology·Adam D Thomas
Oct 24, 2021·Gene·Kailang LiXiaofeng Jin

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Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis