PKCμ prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells

Trauzold, Anna; Schmiedel, Stefan; Sipos, Bence; Wermann, Hendrik; Westphal, Sabine; Röder, Christian; Klapper, Wolfram; Arlt, Alexander; Lehnert, Lasse; Ungefroren, Hendrik; Johannes, Franz‐Josef; Kalthoff, Holger

doi:10.1038/sj.onc.1207001

Cited by 79 publications

(80 citation statements)

References 49 publications

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“…These novel PKC isoenzymes activate PKD1 by transphosphorylation at PKD1 activation loop Ser744 and Ser748 (41,48,50,54). PKD family members have been extensively implicated in the regulation of multiple fundamental biological processes (7,17,35,45). PKDs were also reported to play a critical role in gene transcription by interaction with transcription factors (14,49).…”

Section: Discussionmentioning

confidence: 99%

“…Particularly, the novel isoforms of PKC including ␦, ε, , and have been identified as upstream kinases of PKD1 (42,48,50,54). PKD family members are increasingly implicated in the regulation of multiple cellular functions including protein secretion (7,17), phosphorylation of heat shock protein 27 (53) and histone deacetylase (22), cell proliferation (35), and apoptosis (45). Recent studies revealed that PKDs play a critical role in induction of gene transcription through activation of nuclear transcription factors c-jun (12,49), the cAMP-response element-binding protein (14), and, particularly, NF-B (6,23,(41)(42)(43).…”

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confidence: 99%

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Protein kinase D1 mediates NF-κB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells

Yuan¹,

Lugea²,

Zheng³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Protein kinase D1 mediates NF-κB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells

Yuan¹,

Lugea²,

Zheng³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Moreover there is increased expression of PKD (and CaMKII␦) in failing rat, rabbit, and human myocardium (8,10). Thus, whereas PKD and CaMKII activation may be involved in a wide variety of cell functions (11)(12)(13)(14), they are attractive potential therapeutic targets in cardiac disease. Therapeutic benefit of PKD/CaMKII inhibition may be largely due to prevention of HDAC (class II) phosphorylation, thereby maintaining the repressive effects of HDAC on transcription.…”

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confidence: 99%

Spatiotemporally Distinct Protein Kinase D Activation in Adult Cardiomyocytes in Response to Phenylephrine and Endothelin

Bossuyt

Chang

Helmstadter

et al. 2011

Journal of Biological Chemistry

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Protein kinase D (PKD) is a nodal point in cardiac hypertrophic signaling. It triggers nuclear export of class II histone deacetylase (HDAC) and regulates transcription. Although this pathway is thought to be critical in cardiac hypertrophy and heart failure, little is known about spatiotemporal aspects of PKD activation at the myocyte level. Here, we demonstrate that in adult cardiomyocytes two important neurohumoral stimuli that induce hypertrophy, endothelin-1 (ET1) and phenylephrine (PE), trigger comparable global PKD activation and HDAC5 nuclear export, but via divergent spatiotemporal PKD signals. PE-induced HDAC5 export is entirely PKD-dependent, involving fleeting sarcolemmal PKD translocation (for activation) and very rapid subsequent nuclear import. In contrast, ET1 recruits and activates PKD that remains predominantly sarcolemmal. This explains why PE-induced nuclear HDAC5 export in myocytes is totally PKD-dependent, whereas ET1-induced HDAC5 export depends more prominently on InsP 3 and CaMKII signaling. Thus ␣-adrenergic and ET-1 receptor signaling via PKD in adult myocytes feature dramatic differences in cellular localization and translocation in mediating hypertrophic signaling. This raises new opportunities for targeted therapeutic intervention into distinct limbs of this hypertrophic signaling pathway.Various stresses trigger cardiac hypertrophy, remodeling, and functional alterations (1, 2). Prolonged stress can also become maladaptive, leading to heart failure, cardiac arrhythmias, and sudden death. Many of these changes are mediated by altered gene expression, and Class II histone deacetylases (HDACs) 3 (e.g. HDAC5) are recognized as key modulators of this genetic reprogramming. HDAC5 represses transcription by promoting more condensed DNA, and represses transcription factors such as myocyte enhancing factor 2 (MEF2). HDAC5 phosphorylation triggers its nuclear export (allowing gene activation (Fig. 1a)). Both protein kinase D (PKD) and calmodulin-dependent protein kinase II (CaMKII) are key HDAC kinases (1, 2) and accumulating evidence indicates both kinases are more active in heart failure and can contribute directly to cardiac pathogenesis (3-6). Cardiac PKD is activated in response to hypertension, pressure overload, and chronic neurohumoral signaling (7). Overexpression of constitutively active PKD (and CaMKII␦) cause cardiac hypertrophy followed by chamber dilation (8, 9). Moreover there is increased expression of PKD (and CaMKII␦) in failing rat, rabbit, and human myocardium (8, 10). Thus, whereas PKD and CaMKII activation may be involved in a wide variety of cell functions (11-14), they are attractive potential therapeutic targets in cardiac disease. Therapeutic benefit of PKD/CaMKII inhibition may be largely due to prevention of HDAC (class II) phosphorylation, thereby maintaining the repressive effects of HDAC on transcription. Indeed, HDAC5 knock-out mice develop profound pathological cardiac hypertrophy and HDAC5 overexpression can limit progression of cardiac hypertrophy (15,16)...

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“…Therefore, PKD1 has recently received a considerable attention as a potential therapeutic target for human malignancies. On the other hand, studies focused on PKD1 in human pancreatic ductal adenocarcinoma and basal cell carcinoma have shown an opposing role for PKD1 (33,34). There is even a report that PKD1 expression level was elevated in human prostate carcinoma tissues compared to normal prostate epithelial tissues (35).…”

Section: Discussionmentioning

confidence: 96%

PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma

et al. 2012

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Abstract. Osteosarcoma (OS) is a primary malignancy of the bone, with a tendency to metastasize early. Despite intensive chemotherapy and surgical resection, more than 30% of patients develop distant metastases, and the prognosis of patients with metastases is essentially poor. Members of the protein kinase D (PKD) family are serine/threonine kinases, and have been studied in various cancers. Among the three different isoforms of this family, PKD1 is one of the best understood for its role in human malignancies; however, its role in musculoskeletal tumors has not been studied. In the present study, we investigated the role of PKD1 in human OS. We first analyzed PKD1 mRNA expression in human musculoskeletal tumor tissue samples by quantitative real-time PCR. PKD1 expression in OS samples was significantly lower than that in benign schwannoma samples, and this was correlated with metastatic potential. In in vitro studies, overexpression of PKD1 by plasmid transfection decreased OS cell invasion, migration and proliferation, and significantly decreased matrix metalloproteinase (MMP)2 mRNA expression. Conversely, siRNA knockdown of PKD1 increased invasion, migration and proliferation of OS cells, and MMP2 expression was markedly increased. Furthermore, overexpression of PKD1 significantly reduced in vivo tumor growth of OS cells. These results demonstrated that low expression of PKD1 may contribute to increased cell invasion, migration and proliferation ability of human OS. Taken together, our findings strongly suggest that PKD1 may negatively regulate the malignant potential of human OS, and may be a therapeutic target for human OS in the clinical setting.

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PKCμ prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells

Cited by 79 publications

References 49 publications

Protein kinase D1 mediates NF-κB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells

Protein kinase D1 mediates NF-κB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells

Spatiotemporally Distinct Protein Kinase D Activation in Adult Cardiomyocytes in Response to Phenylephrine and Endothelin

PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma

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