Wild-type p53 inhibits protein kinase CK2 activity

Schuster, Norbert; Götz, Claudia; Faust, Michael; Schneider, Eberhard; Prowald, Alexandra; Jungbluth, Andreas; Montenarh, Mathias

doi:10.1002/1097-4644(20010401)81:1<172::aid-jcb1033>3.0.co;2-o

Cited by 48 publications

(28 citation statements)

References 38 publications

(53 reference statements)

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“…In addition, the manner in which CK2␣1 is activated by hypertrophic stimuli should be clarified. It is known that signals such as Wnt, 36 UV irradiation, 37 or dysinhibition of p53 38 induce the activity of CK2␣1 in cancer. However, it is still unclear whether this signal cascade takes place in tumorigenesis in the same fashion as in the development of cardiac hypertrophy.…”

Section: Eom Et Al Ck2␣1 Phosphorylates Hdac2 S394 For Hypertrophy 2401mentioning

confidence: 99%

Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart

Eom

Cho²,

Ko³

et al. 2011

Circulation

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Background-Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone deacetylases (HDACs) are tightly linked to the regulation of those genes. We previously demonstrated that activation of HDAC2, 1 of the class I HDACs, mediates hypertrophy. Here, we show that casein kinase-2␣1 (CK2␣1)-dependent phosphorylation of HDAC2 S394 is required for the development of cardiac hypertrophy. Methods and Results-Hypertrophic stimuli phosphorylated HDAC2 S394, which was necessary for its enzymatic activation, and therefore the development of hypertrophic phenotypes in rat neonatal cardiomyocytes or in isoproterenoladministered mice hearts. Transgenic mice overexpressing HDAC2 wild type exhibited cardiac hypertrophy, whereas those expressing phosphorylation-resistant HDAC2 S394A did not. Compared with that in age-matched normal human hearts, phosphorylation of HDAC2 S394 was dramatically increased in patients with hypertrophic cardiomyopathy. Hypertrophy-induced phosphorylation of HDAC2 S394 and its enzymatic activity were completely blocked either by CK2 blockers or by CK2␣1 short interfering RNA. Hypertrophic stimuli led CK2␣1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2␣1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2␣1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2␣1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2␣1-transgenic mice were crossed with HDAC2 S394A-transgenic mice. Conclusions-We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394. (Circulation. 2011;123:2392-2403.)Key Words: hypertrophy Ⅲ casein kinase 2 Ⅲ histone deacetylase 2 S394 Ⅲ phosphorylation Ⅲ transgenic mice C ardiac hypertrophy, an increase in the size of cardiomyocytes, is often caused by diverse pathological conditions such as myocardial infarction, hypertension, aortic stenosis, and valvular dysfunction. Although cardiac hypertrophy itself is an initial adaptive process, uncorrected continuous stimuli often lead the heart to heart failure. Because heart failure is a main cause of human mortality, many researchers are eager to develop interventions to reverse cardiac hypertrophy or to prevent the transition to congestive heart failure. Editorial see p 2341 Clinical Perspective on p 2403Posttranslational modifications of histones are closely involved in diverse biological processes through the regulation of transcription of downstream target genes. 1,2 Among these modifications, the acetylation status of the chromatin mediates the epigenetic regulation of gene expression. Two opposing groups of enzymes, histone acetyltransferase and hi...

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Section: Eom Et Al Ck2␣1 Phosphorylates Hdac2 S394 For Hypertrophy 2401mentioning

confidence: 99%

Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart

Eom

Cho²,

Ko³

et al. 2011

Circulation

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“…6A). Collectively, these results can be interpreted as interference by p44 with protein-protein interactions between full-length p53 and CKII, which are known to be inhibitory (Schuster et al 2001), rather than with protein-DNA interactions during assembly of the trans-activation complex on the PTEN promoter. Increased phosphorylation of PTEN by CKII leads not only to its inactivation, but also to its stabilization, which seems to be responsible for the apparent accumulation of phospho-PTEN and loss of degradationsensitive PTEN in cells of p44 mice.…”

Section: Discussionmentioning

confidence: 96%

“…First and foremost, p53 controls the level of the IGF-1 receptor (Werner et al 1996). Secondly, p53 controls both the level and activity of the dual lipid-protein-phosphatase, PTEN (Schuster et al 2001;Stambolic et al 2001). PTEN modulates the IGF signal transduced to Akt, mainly through dephosphorylation of phosphatidyl-inositol triphosphate (Fig.…”

Section: Discussionmentioning

confidence: 99%

Modulation of mammalian life span by the short isoform of p53

Maier¹,

Gluba²,

Bernier³

et al. 2004

Genes Dev.

546

579

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Overexpression of the short isoform of p53 (p44) has unexpectedly uncovered a role for p53 in the regulation of size and life span in the mouse. Hyperactivation of the insulin-like growth factor (IGF) signaling axis by p44 sets in motion a kinase cascade that clamps potentially unimpeded growth through p21Cip1. This suggests that pathways of gene activity known to regulate longevity in lower organisms are linked in mammals via p53 to mechanisms for controlling cell proliferation. Thus, appropriate expression of the short and long p53 isoforms might maintain a balance between tumor suppression and tissue regeneration, a major requisite for long mammalian life span.

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“…Another possibility might be binding of p53 to the cdc25C protein. We have previously shown that wild-type p53 binds to and inhibits a number of proteins directly which are implicated in cell proliferation such as protein kinase CK2 (36,37), cdk1 (18) and cyclin H of the cyclin H/cdk7/Mat1 complex (38). Furthermore, we showed that p53 binds to cdc25C at least in vitro (22).…”

Section: Discussionmentioning

confidence: 81%

Interference between p53 and cdc25C in cell cycle regulation

Ruppenthal

Noll²,

Götz³

et al. 2007

Int J Oncol

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Abstract. The eukaryotic cell cycle is regulated by a network of different protein kinases and phosphatases which are by various mechanisms linked to the growth suppressor p53. Cell cycle regulation is quite similar from yeast to man. Although there is no endogenous p53 in yeast expression of human p53 led to growth arrest of yeast cells which can be suppressed by simultaneous overexpression of cdc25C, a phosphatase regulating entry into mitosis. Herein, we show that overexpression of cdc25C in mammalian cells is insufficient in suppressing a p53 induced growth arrest. We further show that p53 is co-immunoprecipitated with cdc25C and p53 inhibits the cdc25C phosphatase activity in a dose-dependent manner. Thus, our data show that p53 like other binding partners of cdc25C, regulates entry into mitosis by binding to cdc25C.

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Wild-type p53 inhibits protein kinase CK2 activity

Cited by 48 publications

References 38 publications

Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart

Casein Kinase-2α1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart

Modulation of mammalian life span by the short isoform of p53

Interference between p53 and cdc25C in cell cycle regulation

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