Posttranslational modifications regulate HIPK2, a driver of proliferative diseases

Saul, Vera V.; Schmitz, M. Lienhard

doi:10.1007/s00109-013-1042-0

Cited by 39 publications

(41 citation statements)

References 51 publications

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“…Matching results were obtained by counting the number of HIPK2-GFP and K1182-GFP fluorescent cells upon LG and HG conditions (Figure 4F). As HIPK2 may be tightly controlled by hierarchically occurring posttranslational modifications (PTM) [37], we also evaluated whether the HG condition could affect HIPK2 phosphorylation. To this aim, overexpressed HIPK2-GFP protein was immunoprecipitated from cells allowed to stand in either LG or HG condition, before undergoing western immunoblotting with anti-phospho-Ser/Thr antibody.…”

Section: Resultsmentioning

confidence: 99%

Hyperglycemia triggers HIPK2 protein degradation

Baldari¹,

Garufi

Granato

et al. 2016

Oncotarget

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Homeodomain interacting protein kinase-2 (HIPK2) is an evolutionary conserved kinase that modulates several key molecular pathways to restrain tumor growth and induce p53-depending apoptotic cell-death in response to anticancer therapies. HIPK2 silencing in cancer cells leads to chemoresistance and cancer progression, in part due to p53 inhibition. Recently, hyperglycemia has been shown to reduce p53 phosphorylation at serine 46 (Ser46), the target residue of HIPK2, thus impairing p53 apoptotic function. Here we asked whether hyperglycemia could, upstream of p53, target HIPK2. We focused on the effect of high glucose (HG) on HIPK2 protein stability and the underlying mechanisms. We found that HG reduced HIPK2 protein levels, therefore impairing HIPK2-induced p53 apoptotic activity. HG-triggered HIPK2 protein downregulation was rescued by both proteasome inhibitor MG132 and by protein phosphatase inhibitors Calyculin A (CL-A) and Okadaic Acid (OA). Looking for the phosphatase involved, we found that protein phosphatase 2A (PP2A) induced HIPK2 degradation, as evidenced by directly activating PP2A with FTY720 or by silencing PP2A with siRNA in HG condition. The effect of PP2A on HIPK2 protein degradation could be in part due to hypoxia-inducible factor-1 (HIF-1) activity which has been previously shown to induce HIPK2 proteasomal degradation through several ubiquitin ligases. Validation analysed performed with HIF-1α dominant negative or with silencing of Siah2 ubiquitin ligase clearly showed rescue of HG-induced HIPK2 degradation. These findings demonstrate how hyperglycemia, through a complex protein cascade, induced HIPK2 downregulation and consequently impaired p53 apoptotic activity, revealing a novel link between diabetes/obesity and tumor resistance to therapies.

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Section: Resultsmentioning

confidence: 99%

Hyperglycemia triggers HIPK2 protein degradation

Baldari¹,

Garufi

Granato

et al. 2016

Oncotarget

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“…It is well known that HIPK2 is an unstable protein with a high turnover rate in unstressed cells. 25 Thus, we wanted to examine whether PARP1 regulates the protein stability of HIPK2. Protein stability of HIPK2 was monitored with or without PARP1 knockdown following inhibition of protein synthesis using cycloheximide.…”

Section: Resultsmentioning

confidence: 99%

PARP1 regulates the protein stability and proapoptotic function of HIPK2

et al. 2016

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Homeodomain-interacting protein kinase 2 (HIPK2) is a nuclear serine/threonine kinase that functions in DNA damage response and development. In the present study, we propose that the protein stability and proapoptotic function of HIPK2 are regulated by poly(ADP-ribose) polymerase 1 (PARP1). We present evidence indicating that PARP1 promotes the proteasomal degradation of HIPK2. The tryptophan-glycine-arginine (WGR) domain of PARP1 was necessary and sufficient for the promotion of HIPK2 degradation independently of the PARP1 enzymatic activity. The WGR domain mediated the interaction between HIPK2 and C-terminus of HSP70-interacting protein (CHIP) via HSP70. We found that CHIP can function as a ubiquitin ligase for HIPK2. The interaction between PAPR1 and HIPK2 was weakened following DNA damage. Importantly, PARP1 reduced the HIPK2-mediated p53 phosphorylation, proapoptotic transcriptional activity and cell death. These results suggest that PARP1 can modulate the tumor-suppressing function of HIPK2 by regulating the protein stability of HIPK2.

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“…They control a wide spectrum of biological functions such as DNA damage response, apoptosis, hypoxia, cell proliferation and invasion [1, 2, 3, 4]. …”

Section: Introductionmentioning

confidence: 99%

Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies

et al. 2017

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The HIPK2 (serine/threonine homeodomain-interacting protein kinase 2) is a “caretaker” gene, its inactivation increases tumorigenicity while its activation inhibits tumor growth. This report reviews the anti-tumorigenic mechanisms of HIPK2, which include promotion of apoptosis, inhibition of angiogenesis in hypoxia, prevention of tumor invasion/metastasis and attenuation of multidrug resistance in cancer. Additionally, we summarize conditions or factors that may increase HIPK2 activity.

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Posttranslational modifications regulate HIPK2, a driver of proliferative diseases

Cited by 39 publications

References 51 publications

Hyperglycemia triggers HIPK2 protein degradation

Hyperglycemia triggers HIPK2 protein degradation

PARP1 regulates the protein stability and proapoptotic function of HIPK2

Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies

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