Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Yoshida, Kiyotsugu; Liu, Hanshao; Miki, Yoshio

doi:10.1074/jbc.m512074200

Cited by 167 publications

(150 citation statements)

References 32 publications

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“…This is in line with the concept that efficient induction of proapoptotic genes requires p53 interaction with different cofactors (Vousden and Liu, 2002). Moreover, as several kinases have been claimed to phosphorylate p53 at Ser46, including ATM , DNAdependent protein kinase (Komiyama et al, 2004), protein kinase C d (Yoshida et al, 2006) and dualspecificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) (Taira et al, 2007), the fact that only HIPK2 can drive Lys382 acetylation renders this kinase a unique and complex regulator of p53 apoptotic function (Figure 3). One important finding that supports the relationship between HIPK2, p53 and p300 for p53 apoptotic function comes from a leukemogenesis model in which the oncogene CBFb-SMMHC attenuates the p53 apoptotic function in response to DNA damage (that is, g-irradiation and VP-16) (Britos-Bray et al, 1998).…”

Section: Role Of Hipk2 In P53 Acetylationsupporting

confidence: 76%

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: Role Of Hipk2 In P53 Acetylationsupporting

confidence: 76%

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

et al. 2010

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“…In vitro kinase assays were performed as described (Yoshida and Kufe, 2001;Yoshida et al, 2002bYoshida et al, , 2006a. Briefly, recombinant GST-c-Abl(683-790) proteins corresponding to wild type and T735A purified from plasmid-transduced E. coli were incubated in kinase buffer (20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, pH 7.0, 10 mM MgCl 2 , 0.1 mM Na 3 VO 4 and 2 mM dithiothreitol) with recombinant GST-CLK1, GST-CLK4, GST-MST1, His-MST2 or GST-TTK protein (Invitrogen, Carlsbad, CA, USA) and ATP for 20 min at 30 1C.…”

Section: In Vitro Kinase Assaysmentioning

confidence: 99%

TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress

et al. 2008

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Upon exposure to genotoxic stress, the c-Abl tyrosine kinase is released from cytoplasmic 14-3-3 proteins and then is targeted to the nucleus. Phosphorylation of Thr735 in c-Abl is critical for binding to 14-3-3; however, kinases responsible for this phosphorylation are unknown. Here, we identify CLK1, CLK4, MST1, MST2 and TTK (also known as Mps1) as novel Thr735 kinases in vitro by expression cloning strategy using phosphospecific antibody. We also demonstrate that ectopic expression of these kinases is capable for phosphorylation of Thr735 in cells. Importantly, upon exposure to oxidative stress, phosphorylation of Thr735 is transiently upregulated, and the status of this phosphorylation remains unchanged in cells silenced for CLK1, CLK4, MST1 or MST2. By contrast, knockdown of TTK attenuates phosphorylation of Thr735, suggesting that TTK is a physiological kinase that phosphorylates Thr735. In concert with these results, we show that, in cells silenced for TTK, c-Abl is accumulated in the nucleus even in unstressed condition and no further targeting into the nucleus occurs after oxidative stress. Moreover, nuclear entrapment of c-Abl by knocking down TTK enhances oxidative stress-induced apoptosis. These findings provide evidence that TTK phosphorylates c-Abl at Thr735 and that this phosphorylation is of importance to the cytoplasmic sequestration of c-Abl.

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“…TP53INP1 is also known to interact physically with two different kinases: the Homeodomain-interacting protein kinase-2 and the pro-apoptotic Protein Kinase C d contributing to the regulation of p53 activity (Tomasini et al, 2003;Yoshida et al, 2006). The E2F1 transcription factor, which is also a major player in cell proliferation and apoptosis, is involved in TP53INP1 transcriptional regulation (Hershko et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression

et al. 2011

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Tumor protein 53 induced nuclear protein 1 (TP53INP1) is a p53 target gene that induces cell growth arrest and apoptosis by modulating p53 transcriptional activity. TP53INP1 interacts physically with p53 and is a major player in the p53-driven oxidative stress response. Previously, we demonstrated that TP53INP1 is downregulated in an early stage of pancreatic cancerogenesis and when restored is able to suppress pancreatic tumor development. TP53INP1 downregulation in pancreas is associated with an oncogenic microRNA miR-155. In the present work, we studied the effects of TP53INP1 on cell migration. We found that TP53INP1 inactivation correlates with increased cell migration both in vivo and in vitro. The impact of TP53INP1 expression on cell migration was studied in different cellular contexts: mouse embryonic fibroblast and different pancreatic cancer cell lines. Its expression decreases cell migration by the transcriptional downregulation of secreted protein acidic and rich in cysteine (SPARC). SPARC is a matrix cellular protein, which governs diverse cellular functions and has a pivotal role in regulating cell-matrix interactions, cellular proliferation and migration. SPARC was also showed to be upregulated in normal pancreas and in pancreatic intraepithelial neoplasia lesions in a pancreatic adenocarcinoma mouse model only in the TP53INP1-deficient animals. This novel TP53INP1 activity on the regulation of SPARC expression could explain in part its tumor suppressor function in pancreatic adenocarcinoma by modulating cellular spreading during the metastatic process.

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Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Cited by 167 publications

References 32 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

TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress

TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression

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