Two Faces of Protein Kinase Cδ: The Contrasting Roles of PKCδ in Cell Survival and Cell Death

Basu, Alakananda; Pal, Deepanwita

doi:10.1100/tsw.2010.214

Cited by 119 publications

(129 citation statements)

References 100 publications

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“…4,12 Numerous studies have shown that PKCd is involved in proapoptic signaling upon phorbol ester stimulation and after DNA damage. 13 Therefore, we tested PMAinduced cell death in the patient's cells (EBV-transformed B cells and PBMCs). Although treatment with PMA induced 60% and 50% cell death in EBV-transformed B cells (Figure 6A-B) and PBMCs from normal control patients ( Figure 6C), respectively, the patient's cells were completely resistant to BLOOD, 18 APRIL 2013 x VOLUME 121, NUMBER 16 PKCd DEFICIENCY CAUSES ALPS-LIKE DISEASE 3121…”

Section: Pma-induced Apoptosis Is Defective In Pkcd Deficiencymentioning

confidence: 99%

Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans

Kuehn

Niemela

Rangel-Santos

et al. 2013

Blood

126

105

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• Mutations in PRKCD cause a syndrome characterized by chronic benign lymphadenopathy, positive autoantibodies, and NK dysfunction.• PRKCD deficiency disrupts control of B-cell proliferation and apoptosis and affects NK-cell cytolytic activity.Defective lymphocyte apoptosis results in chronic lymphadenopathy and/or splenomegaly associated with autoimmune phenomena. The prototype for human apoptosis disorders is the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic pathway. Recently, patients with an ALPS-like disease called RAS-associated autoimmune leukoproliferative disorder, in which somatic mutations in NRAS or KRAS are found, also were described. Despite this progress, many patients with ALPS-like disease remain undefined genetically. We identified a homozygous, loss-of-function mutation in PRKCD (PKCd) in a patient who presented with chronic lymphadenopathy, splenomegaly, autoantibodies, elevated immunoglobulins and natural killer dysfunction associated with chronic, low-grade Epstein-Barr virus infection. This mutation markedly decreased protein expression and resulted in ex vivo B-cell hyperproliferation, a phenotype similar to that of the PKCd knockout mouse. Lymph nodes showed intense follicular hyperplasia, also mirroring the mouse model. Immunophenotyping of circulating lymphocytes demonstrated expansion of CD51CD201 B cells. Knockdown of PKCd in normal mononuclear cells recapitulated the B-cell hyperproliferative phenotype in vitro. Reconstitution of PKCd in patient-derived EBV-transformed B-cell lines partially restored phorbol-12-myristate-13-acetate-induced cell death. In summary, homozygous PRKCD mutation results in B-cell hyperproliferation and defective apoptosis with consequent lymphocyte accumulation and autoantibody production in humans, and disrupts natural killer cell function. (Blood. 2013;121(16):3117-3125)

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Section: Pma-induced Apoptosis Is Defective In Pkcd Deficiencymentioning

confidence: 99%

Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans

Kuehn

Niemela

Rangel-Santos

et al. 2013

Blood

126

105

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“…It is generally believed that the activation of PKC isoforms contributes to cancer, but downregulation rather than activation of PKCd has been associated with tumor progression (7). While some studies point to a role of PKCd in cell survival and the antiapoptotic response, most studies indicate that the PKCd isoform promotes suppression of cell proliferation and apoptosis induction.…”

Section: Introductionmentioning

confidence: 99%

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Flores

Castilla

Gasca

et al. 2016

Molecular Cancer Therapeutics

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Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCd silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKCd seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/b-catenin pathway. PKCd silencing induces activation of Wnt/b-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3b inactivation and consequently in the stabilization of b-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/b-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCd. Finally, we observe that high Gleason score prostate tumors lose PKCd expression and this correlates with higher activation of b-catenin, inactivation of GSK3b, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/b-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCd expression.

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“…42 We found that both Bcl-xL and Bax expressions are significantly modulated in differentiating MKs, with a kinetic similar to PKCε and PKCδ, respectively ( Figure 1A,C).…”

Section: Pkcδ/pkcε and Bax/bcl-xl Expression Levels Are Differently Mmentioning

confidence: 77%

Human thrombopoiesis depends on Protein kinase C /protein kinase C functional couple

et al. 2016

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Two Faces of Protein Kinase Cδ: The Contrasting Roles of PKCδ in Cell Survival and Cell Death

Cited by 119 publications

References 100 publications

Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans

Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Human thrombopoiesis depends on Protein kinase C /protein kinase C functional couple

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