HIPK2: A tumour suppressor that controls DNA damage‐induced cell fate and cytokinesis

Hofmann, Thomas G.; Glas, Carolina; Bitomsky, Nadja

doi:10.1002/bies.201200060

Cited by 73 publications

(71 citation statements)

References 92 publications

(133 reference statements)

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“…The Ser/Thr protein kinase homeodomain interacting protein kinase 2 (HIPK2) is an evolutionarily conserved regulator of cell death and cell growth during development and in response to cellular stress (5,6). There is growing evidence that HIPK2 acts as a tumor suppressor both in mice and men (7)(8)(9)(10) and that the kinase is functionally deregulated by cellular and candidate viral oncogenes (11).…”

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Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death

Bitomsky

Conrad

Moritz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. Moreover, HIPK2 autophosphorylation is conserved between human and zebrafish and is important for DNA damage-induced apoptosis in vivo. Mechanistically, autophosphorylation creates a binding signal for the phospho-specific isomerase Pin1. Pin1 links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1-HIPK2 interaction. Concordantly, Pin1 is required for DNA damage-induced HIPK2 stabilization and p53 Ser46 phosphorylation and is essential for induction of apotosis both in cellulo and in zebrafish. Our results identify an evolutionary conserved mechanism regulating DNA damage-induced apoptosis.

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confidence: 99%

Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death

Bitomsky

Conrad

Moritz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Among the known binding partners of Hipk2 are Trp53, C-terminal binding protein 1 (Ctbp1), c-Myb, p300, Hmga1, Zyxin, H2B, Pc2, β-catenin, Siah2, and MeCP2 (1,2). Despite this plethora of pathways linked to Hipk2, the known consequences of Hipk2 deletion in the mouse germ line are relatively modest (3)(4)(5), including an expansion of trigeminal sensory neurons (4) and altered maturation of dopaminergic neurons (5).…”

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confidence: 99%

“…Despite this plethora of pathways linked to Hipk2, the known consequences of Hipk2 deletion in the mouse germ line are relatively modest (3)(4)(5), including an expansion of trigeminal sensory neurons (4) and altered maturation of dopaminergic neurons (5). Hipk2 has also been implicated in cancer development, either as a suppressor of skin tumors and lymphoma or as an oncogene amplified in pilocytic astrocytomas, but the mechanisms that underlie these phenotypes are not known (1,2,(6)(7)(8).…”

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“…T he highly conserved serine/threonine nuclear kinase homeodomain-interacting protein kinase 2 (Hipk2), in common with many transcriptional coactivators, corepressors, and kinases, affects the expression of multiple genes involved in a broad spectrum of signaling pathways (1,2). Among the known binding partners of Hipk2 are Trp53, C-terminal binding protein 1 (Ctbp1), c-Myb, p300, Hmga1, Zyxin, H2B, Pc2, β-catenin, Siah2, and MeCP2 (1,2).…”

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Identification of Hipk2 as an essential regulator of white fat development

Sjölund

Pelorosso

Quigley

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Homeodomain-interacting protein kinase 2 (Hipk2) has previously been implicated in the control of several transcription factors involved in embryonic development, apoptosis, cell proliferation, and tumor development, but very little is understood about the exact mechanisms through which Hipk2 influences these processes. Analysis of gene expression in normal tissues from genetically heterogeneous mouse or human populations can reveal network motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function.Here we have applied this network strategy to uncover a role for the Hipk2 gene in the transcriptional system controlling adipogenesis. Both in vitro and in vivo models were used to show that knockdown or loss of Hipk2 specifically inhibits white adipose cell differentiation and tissue development. In addition, loss of Hipk2 leads to induction of pockets of multilocular brown fat-like cells in remaining white adipose depots, which express markers of brown and beige fat such as uncoupling protein 1 and transmembrane protein 26. These changes are accompanied by increased insulin sensitivity in Hipk2 knockout mice and reduced high-fat dietinduced weight gain, highlighting a potential role for this kinase in diseases such as diabetes and obesity. Our study underscores the versatility and power of a readily available tissue, such as skin, for network modeling of systemic transcriptional programs involved in multiple pathways, including lipid metabolism and adipogenesis.

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“…1 Homeodomain interacting kinase 2 (HIPK2) is a multifunctional signaling molecule and tumor suppressor mediating growth-regulatory and apoptotic cellular responses. 8 The kinase is involved in numerous signaling pathways, including Wnt signaling, hypoxic response, and DNA damage response. [9][10][11] Among those, the best-studied function is its role in DNA damage-activated signaling.…”

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confidence: 99%