Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription

Xl, Li; Arai, Yasuhito; Harada, Hironori; Shima, Yutaka; Yoshida, Hitoshi; Rokudai, Susumu; Aikawa, Yuri; Kimura, Akiro; Kitabayashi, Issay

doi:10.1038/sj.onc.1210523

Cited by 63 publications

(51 citation statements)

References 61 publications

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“…Very few studies report HIPK2 transcriptional downregulation, for instance in thyroid, breast (Pierantoni et al, 2002) and colorectal carcinoma specimens (D 'Orazi et al, 2006), although these findings still need extended functional studies. Two missense mutations were identified in human acute myeloid leukemias (AMLs), which led to aberrant distribution of HIPK2 within the nucleus with impaired transcription by AML1 and p53 transcription factors (Li et al, 2007b). However, in that study, HIPK2 was found mutated in a very small percentage (2 out of 130 cases) so that it is difficult to justify a connection with p53 inactivation.…”

Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionmentioning

confidence: 89%

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

et al. 2010

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The p53 protein is the most studied tumor suppressor and the p53 pathway has been shown to mediate cellular stress responses that are disrupted when cancer develops. After DNA damage, p53 is activated as transcription factor to directly induce the expression of target genes involved in cell-cycle arrest, DNA repair, senescence and, importantly, apoptosis. Post-translational modifications of p53 are essential for the activation of p53 and for selection of target genes. The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating its N-terminal serine 46 (Ser46) and facilitating Lys382 acetylation at the C-terminus. HIPK2 is activated by numerous genotoxic agents and can be deregulated in tumors by several conditions including hypoxia. Recent findings suggest that HIPK2 active/inactive protein can affect p53 function in multiple and unexpected ways. This makes p53 as well as HIPK2 interesting targets for cancer therapy. Hence, understanding the role of HIPK2 as p53 activator may provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer.

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Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionmentioning

confidence: 89%

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

et al. 2010

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“…53 Indeed, 2 mutations at the speckle-retention signal domain of HIPK2, resulting in abnormal subcellular localization, have recently been reported in AML patients. 54 Therefore, the profound alteration in HIPK2 cellular distribution induced by RUNX1/␤-SMMHC would, in all probability, disrupt normal HIPK2 functions.…”

Section: Discussionmentioning

confidence: 99%

PEBP2-β/CBF-β–dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis

Wee

Voon

Bae

et al. 2008

Blood

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The heterodimeric transcription factor RUNX1/PEBP2-␤ (also known as AML1/ CBF-␤) is essential for definitive hematopoiesis. Here, we show that interaction with PEBP2-␤ leads to the phosphorylation of RUNX1, which in turn induces p300 phosphorylation. This is mediated by homeodomain interacting kinase 2 (HIPK2), targeting Ser 249 , Ser 273 , and Thr 276 in RUNX1, in a manner that is also dependent on the RUNX1 PY motif. Importantly, we observed the in vitro disruption of this phosphorylation cascade by multiple leukemogenic genetic defects targeting RUNX1/CBFB. In particular, the oncogenic protein PEBP2-␤-SMMHC prevents RUNX1/p300 phosphorylation by sequestering HIPK2 to mislocalized RUNX1/ ␤-SMMHC complexes. Therefore, phosphorylation of RUNX1 appears a critical step in its association with and phosphorylation of p300, and its disruption may be a common theme in RUNX1-associated leukemogenesis. (Blood. 2008;112:3777-3787) IntroductionThe runt-related transcription factor RUNX1 (AML1; PEBP2-␣; CBF-␣) and its non-DNA binding partner PEBP2-␤/CBF-␤ are frequent targets of leukemogenic genetic changes. [1][2][3] The heterodimer plays a critical role in definitive hematopoiesis, and disruption of its normal function by chromosomal abnormalities or mutations is collectively the most common cause of acute myeloid leukemia (AML). Their central role in orchestrating proper differentiation of hematopoietic stem cells is underscored by the ablation of definitive hematopoiesis in Runx1 or Pebp2b Ϫ/Ϫ knockout mice [4][5][6] and an expanded HSC compartment in conditional Runx1-deficient mice. [7][8][9][10] However, although the overall biologic functions of RUNX1 are becoming clear, how these functions are controlled at the molecular level and the contribution of PEBP2-␤ remain to be fully determined.The evolutionarily conserved partner protein PEBP2-␤ is known to enhance DNA binding ability of all 3 mammalian RUNX proteins (RUNX1-3) by inducing allosteric change of DNA binding Runt domain without direct DNA contact. In addition, we have previously reported that PEBP2-␤ regulates RUNX1 metabolic stability by preventing its ubiquitin-mediated degradation. 11 It has also been speculated that PEBP2-␤ may also function to recruit other proteins to the target gene promoter, although only 2 cytoplasmic proteins, Crl-1 and filamin A, have ever been reported to interact with PEBP2-␤. 12-15 Notwithstanding our current incomplete understanding of molecular interaction between PEBP2-␤ and RUNX1, it is clear that PEBP2-␤ is essential for RUNX1 function in vivo, as Pebp2␤-deficient mice exhibit a very similar phenotype to Runx1 Ϫ/Ϫ mice. [4][5][6] Whereas early studies have implicated RUNX1 to be a transcriptional activator, subsequent studies revealed more diverse and intricate functions. It is now clear that RUNX1 can also act as a transcriptional repressor and functions as a molecular scaffold for the organization of partner transcription factors and cofactors at the regulatory regions of target genes. RUNX1 interacts with a growing lis...

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“…An interesting possibility would be that HIPK2 acts on the organization of chromatin to facilitate DNA repair (Supplementary Figure 4). Abnormal DNA repair, or abnormal epigenetic maintenance, could both contribute to the tumorigenic potential of cells lacking HIPK2 (Li et al, 2007;Wei et al, 2007).…”

Section: Hipk2 Phosphorylates and Downregulates Zbtb4mentioning

confidence: 99%

The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4

et al. 2009

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HIPK2 is a eukaryotic Serine-Threonine kinase that controls cellular proliferation and survival in response to exogenous signals. Here, we show that the human transcription factor ZBTB4 is a new target of HIPK2. The two proteins interact in vitro, colocalize and associate in vivo, and HIPK2 phosphorylates several conserved residues of ZBTB4. Overexpressing HIPK2 causes the degradation of ZBTB4, whereas overexpressing a kinasedeficient mutant of HIPK2 has no effect. The chemical activation of HIPK2 also decreases the amount of ZBTB4 in cells. Conversely, the inhibition of HIPK2 by drugs or by RNA interference causes a large increase in ZBTB4 levels. This negative regulation of ZBTB4 by HIPK2 occurs under normal conditions of cell growth. In addition, the degradation is increased by DNA damage. These findings have two consequences. First, we have recently shown that ZBTB4 inhibits the transcription of p21. Therefore, the activation of p21 by HIPK2 is twopronged: stimulation of the activator p53, and simultaneous repression of the inhibitor ZBTB4. Second, ZBTB4 is also known to bind methylated DNA and repress methylated sequences. Consequently, our findings raise the possibility that HIPK2 might influence the epigenetic regulation of gene expression at loci that remain to be identified.

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Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription

Cited by 63 publications

References 61 publications

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

PEBP2-β/CBF-β–dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis

The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4

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