Sp100 is important for the stimulatory effect of homeodomain-interacting protein kinase-2 on p53-dependent gene expression

Möller, Andreas; Sirma, Hüseyin; Hofmann, Thomas G.; Staege, Hannah; Gresko, Ekaterina; Lüdi, Katharina Schmid; Klimczak, Elisabeth; Dröge, Wulf; Will, Hans; Schmitz, M. Lienhard

doi:10.1038/sj.onc.1207079

Cited by 42 publications

(36 citation statements)

References 30 publications

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“…Some small HIPK2 foci remained intact and did not overlap with ZBTB4. A kinase-inactive version of HIPK2 (mutant K221A, Figure 2c) was nuclear but not recruited into foci, as published (Moller et al, 2003). This mutant protein broadly colocalized with ZBTB4.…”

Section: Identification Of Hipk2 As a Zbtb4 Interactorsupporting

confidence: 63%

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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Section: Identification Of Hipk2 As a Zbtb4 Interactorsupporting

confidence: 63%

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

et al. 2009

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“…Several of the interferon-responsive genes under negative Notch control in keratinocytes have been previously implicated in positive growth control, apoptosis, and/or tumorigenesis (e.g., see Ghosh et al 2001;Carpten et al 2002;Wasylyk et al 2002;Zhang and Pagano 2002), with an impact that is likely to extend to keratinocytes. We note in particular the down-modulation of Sp100, a key component of nuclear bodies involved in chromatin control (Moller et al 2003), which parallels the opposite up-regulation of PML, another nuclear body component, in cells with loss of p63 expression (Bernassola et al 2005;Keyes et al 2005). While we have focused on IRF7 for direct functional studies and shown that IRF7 overexpression is sufficient to relieve Notch-dependent suppression of expression of p63, the endogenous IRF7 protein is likely to function in concert with other interferon-responsive genes in regulation of p63 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Among the suppressed genes in human cells were the ones for IRF7, a key regulator of the interferon-dependent transcription cascade with oncogenic potential (Zhang and Pagano 2002;Honda et al 2005), and Sp100, an essential component of nuclear bodies (NBs) ( Fig. 3D; Moller et al 2003), while in the mouse cells down-modulation was observed for IRF3, which physically interacts and functionally overlaps with IRF7 (Servant et al 2002), and IKK , a key kinase that positively regulates the interferon response ( Fig. 3F; Fitzgerald et al 2003).…”

Section: Notch Activation Suppresses P63 Expression Through Negative mentioning

confidence: 99%

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

351

411

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Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Normal tissue homeostasis is determined by a complex interplay between developmental signals and other cell regulatory pathways. Notch cell surface receptors and their ligands belonging to the Delta and Serrate/Jagged families play a crucial role in cell fate determination and differentiation, functioning in a cell-and context-specific manner (Artavanis-Tsakonas et al. 1999). In mammalian cells, Notch activation is generally thought to maintain stem cell potential and inhibit differentiation, thereby promoting carcinogenesis (Artavanis-Tsakonas et al. 1999). However, in specific cell types such as keratinocytes, increased Notch activity causes exit from the cell cycle and commitment to differentiation (Lowell et al. 2000;Rangarajan et al. 2001;Nickoloff et al. 2002), whereas down-modulation or loss of Notch1 function promotes carcinogenesis (Talora et al. 2002;Nicolas et al. 2003).In the human epidermis, localized expression of the Notch-ligand Delta in putative "stem cells" has been proposed to induce commitment of neighboring Notch1-expressing keratinocytes to a "transit-amplifying" phenotype, through a negative feedback mechanism of lateral inhibition (Lowell et al. 2000). On the other hand, in both mouse and human epidermis, Jagged 1/2, Notch1, and Notch2 are coexpressed in differentiating keratinocytes of the supra-basal layers, consistent with a positive feedback loop between these molecules that serves to reinforce and synchronize Notch activation with differentiation (Luo et al. 1997;Rangarajan et al. 2001;Nickoloff et al. 2002).The best characterized "canonical" pathway of Notch activation involves proteolytic cleavage and translocation of the cytoplasmic domain of the receptor to the nucleus, where it associates with the DNA-binding protein RBP-J (CBF-1, CSL), converting it from a repressor

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“…Besides PML, other proteins function as cofactors for HIPK2-mediated p53Ser46 phosphorylation by binding to p53 and HIPK2. These include the PML-nuclear body components Sp100 (Moller et al, 2003b) and the death domain-associated protein Daxx (Li et al, 2007a), the p53-inducible factor p53DINP1/ TP53INP1 (Okamura et al, 2001;Tomasini et al, 2003) and Axin (Rui et al, 2004), a master scaffold for the regulation of the Wnt/b-catenin signaling pathway (Kikuchi, 1999;Peifer and Polakis, 2000) ( Figure 2). Axin (amino acids 678-753) physically interacts with HIPK2 (amino acids 935-1050) as well as p53-activating HIPK2-mediated p53Ser46 phosphorylation and facilitates p53-dependent transcriptional activity and apoptosis (Rui et al, 2004).…”

Section: Hipk2 Phosphorylates P53 At Ser46 and Mediates Apoptosismentioning

confidence: 99%

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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Sp100 is important for the stimulatory effect of homeodomain-interacting protein kinase-2 on p53-dependent gene expression

Cited by 42 publications

References 30 publications

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

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

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

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

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