HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism

Conrad, Elisa; Polonio-Vallon, Tilman; Meister, Michael T.; Matt, Sonja; Bitomsky, Nadja; Herbel, Christoph; Liebl, Magdalena C.; Greiner, Vera; Križnik, Bojana; Schumacher, S.; Krieghoff-Henning, Eva; Hofmann, Thomas G.

doi:10.1038/cdd.2015.75

Cited by 64 publications

(53 citation statements)

References 63 publications

(114 reference statements)

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“…HIPK2 interacts and phosphorylates SIRT1 at Ser682 after DNA damage. Phosphorylation of SIRT1 inhibits SIRT1 deacetylase activity on p53 which in turn potentiates apoptotic p53 target gene expression and DNA damage-induced apoptosis (Conrad et al 2015). SIRT1 is also ubiquitinated by MDM2 during DDR, and ubiquitination of SIRT1 affects its function in cell death and survival in response to DNA damage (Peng et al 2015).…”

Section: Possible Mechanisms Of Hdacs In Cancer Developmentmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

920

765

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Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Post-translational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling and nuclear architecture. Histone acetylation, a well-studied post-translational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous non-histone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.

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Section: Possible Mechanisms Of Hdacs In Cancer Developmentmentioning

confidence: 99%

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Seto

2016

Cold Spring Harb Perspect Med

920

765

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“…P53 plays a vital role in the apoptotic signaling pathways, including membrane apoptotic signaling and mitochondrial apoptotic pathways, and affects the transcription and expression of many apoptosis-related cytokines in the nucleus [41]. SIRT1 reduces the transcriptional activity of p53, and blocks p53-dependent cell apoptosis caused by DNA damage [42].…”

Section: Discussionmentioning

confidence: 99%

Bone mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

Zhou

Qiao

Liu

et al. 2020

Preprint

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Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI).The main drawbacks of MSC therapy including the lack of specific homing following systemic infusion and early death of the cells in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning promotes the therapeutic effect of the MSCs, although the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO on bone marrow mesenchymal stem cells (BMSCs) for the treatment of AKI. ResultsWe found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in the BMSCs, which was decreased following EPO pretreatment indicating that EPO protected the cells from apoptosis. Further, we found that EPO upregulated SIRT1 and Bcl-2 expression, and downregulated p53 expression. The EPO-mediated antiapoptotic mechanism in pretreated BMSCs may be mediated though the SIRT1 pathway. In a rat AKI model, our data showed that 24 h following intravenous infusion, GFP-BMSCs were predominantly in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs, and increased the distribution of the BMSCs to the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-a and significantly higher level of IL-10 compared to rats infused with BMSCs. The administration of EPO-BMSCs after reperfusion was more effective in reducing serum creatinine, blood urea nitrogen, and pathological scores in the I/R-AKI rats than BMSCs.Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs in improving renal function and pathological presentation in I/R-AKI rats. BackgroundAcute kidney injury (AKI) is one of the most clinically impactful diseases with high morbidity and mortality [1,2]. Multiple injuries such as those resulting from sepsis, ischemia/reperfusion (I/R), and drug administration may induce AKI. I/R injury is a major cause of human AKI, which is associated with tubular necrosis, cast formation, tubular dilation, loss of brush border, and inflammation [3]. AKI remains a worldwide public health concern due to the increased risk for subsequent development of 4 chronic kidney disease (CKD) [4]. The annual medical expenses associated with AKI treatment places a heavy burden on the public health care system, and yet AKI lacks an established treatment strategy. Therefore, there is an urgent need to find innovative and effective therapeutic strategies for AKI. The application of mesenchymal stem cells (MSCs) has been suggested as a potentially promising treatment strategy for AKI [5,6].In the recent years, MSCs have become an area of intense research in the field of stem cell therapy.MSCs are adherent, fibroblast-like cells, derived from different tissues and organs including bone marrow, umbilical cord blood, adipose tissue, and solid organs that have the potential for multidirectional diff...

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“…The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing acetylation of p53 [76]. Conrad et al found that DNA damage initiates interaction between SIRT1 and HIPK2, which phosphorylates SIRT1 at Ser682 in response to lethal damage [54]. Phosphorylation of Ser682 inhibits SIRT1 activity in p53 acetylation and impacts expression of apoptotic p53 target genes and apoptosis.…”

Section: Roles Of Hipk2 In Ddrmentioning

confidence: 99%

Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome

Kuwano

Nishida

Akaike

et al. 2016

IJMS

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Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that phosphorylates and activates the apoptotic program through interaction with diverse downstream targets including tumor suppressor p53. HIPK2 is activated by genotoxic stimuli and modulates cell fate following DNA damage. The DNA damage response (DDR) is triggered by DNA lesions or chromatin alterations. The DDR regulates DNA repair, cell cycle checkpoint activation, and apoptosis to restore genome integrity and cellular homeostasis. Maintenance of the DDR is essential to prevent development of diseases caused by genomic instability, including cancer, defects of development, and neurodegenerative disorders. Recent studies reveal a novel HIPK2-mediated pathway for DDR through interaction with chromatin remodeling factor homeodomain protein 1γ. In this review, we will highlight the molecular mechanisms of HIPK2 and show its functions as a crucial DDR regulator.

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HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism

Cited by 64 publications

References 63 publications

HDACs and HDAC Inhibitors in Cancer Development and Therapy

HDACs and HDAC Inhibitors in Cancer Development and Therapy

Bone mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome

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