Disease relevance of Prkcd

• Taken together, these results demonstrate that activation of PKCdelta triggers degradation of MKP-1 through the ubiquitin-proteasome pathway, thereby contributing to persistent activation of ERK1/2 under glutamate-induced oxidative toxicity [1].
• Furthermore, the PKC-delta-deficient mice contain circulating autoreactive antibodies and display immune-complex-type glomerulonephritis, as well as lymphocyte infiltration in many organs [2].
• Here we describe studies with mice lacking protein kinase Cdelta (PKCdelta) showing that absence of this enzyme markedly reduces reperfusion injury following transient ischemia [3].
• Total body irradiation followed by transplantation with bone marrow from PKCdelta-null mice donors reduced infarct size and improved neurological outcome in WT mice, whereas marrow transplantation from WT donors increased infarction and worsened neurological scores in PKCdelta-null mice [3].
• Activation of protein kinase C-delta (PKC-delta) by 12-O-tetradecanoylphorbol-13-acetate (TPA) is followed by a gradual decrease in detectable protein 12-24 h later in the mouse B lymphoma cell line A20 [4].

High impact information on Prkcd

• Production of interleukin-6 was markedly increased in B cells of PKC-delta-null mice as a result of an increase in the DNA-binding activity of NF-IL6 [2].
• The rate of proliferation in response to stimulation was greater for B cells from PKC-delta-deficient mice than for those from wild-type mice [2].
• Among the PKC isotypes, PKC-delta is unique in that its overexpression results in inhibition of cell growth [2].
• These phenotypes correlated with increased PKC delta expression in c-abl-/- osteoblasts and decreased PKC delta expression in Atm-/- cells, respectively [5].
• UV-induced rapid and robust activation of JNK requires PKCdelta, which augments JNK phosphorylation-activation by its upstream kinases [6].

Chemical compound and disease context of Prkcd

• Caspase-2, PKCdelta, and JNK were furthermore implicated in doxorubicin-induced apoptosis of primary acute lymphoblastic leukemia blasts [7].
• Western blot analysis, using isoform-specific anti-PKC antibodies showed that under our culture conditions C6 glioma cells express the conventional isoforms PKC alpha, PKC gamma, as well as the novel isoforms PKC delta, PKC epsilon, and the atypical isoforms PKC lambda and PKC iota [8].
• Kainate-induced neuronal death was significantly increased by pharmacological inhibition of PKC-delta with rottlerin, suggesting a protective role of PKC-delta against kainate toxicity [9].
• Apoptosis of murine melanoma B16-BL6 cells induced by quercetin targeting mitochondria, inhibiting expression of PKC-alpha and translocating PKC-delta [10].
• Our results indicate that PKCdelta protects glioma cells from the apoptosis induced by TRAIL and implicate the phosphorylation of PKCdelta on tyrosine 155 and its cleavage as essential factors in the anti-apoptotic effect of PKCdelta [11].

Biological context of Prkcd

• Transient-transfection assays with NIH 3T3 cells, using an SRE-driven luciferase reporter plasmid, indicated that PKC-alpha and PKC-epsilon, but not PKC-delta or PKC-zeta, mediate SRE activation [12].
• The results indicate that UVR-mediated signal transduction pathway to the induction of SCC does not seem to be sensitive to PKCdelta overexpression [13].
• UVB-induced activation of extracellular signal-regulated protein kinases (Erks) and c-Jun NH2-terminal kinases (JNKs) was strongly inhibited by DNM PKCepsilon and PKCdelta, whereas the DNM of PKCalpha was less effective on the UVB-induced phosphorylation of Erks and JNKs [14].
• These data demonstrate that PKCdelta and PKCepsilon, but not PKCalpha, mediate UVB-induced signal transduction and apoptosis in JB6 cells through activation of Erks and JNKs [14].
• Furthermore, rottlerin, an inhibitor of protein kinase Cdelta (PKCdelta) and calmodulin kinase III, abrogated the up-regulation at both protein and mRNA levels [15].

Anatomical context of Prkcd

• IGF-1 also selectively induced translocation of PKCdelta and PKCepsilon from soluble to particulate fractions in mouse keratinocytes [16].
• This study showed that UVB markedly induced translocation of membrane-associated PKCepsilon and PKCdelta, but not PKCalpha, from cytosol to membrane [14].
• Our results suggest that PKCdelta activation is responsible for a major part of EGF-induced fibroblast contractile force generation [17].
• Similarly, c-Jun amino-terminal kinase activation is suppressed in vivo in gamma-irradiated parotid glands from PKCdelta(-/-) mice [18].
• In this article we show that PKCzeta but not PKCalpha and PKCdelta can co-immunoprecipitate PKB from CHO cell lysates [19].

Associations of Prkcd with chemical compounds

• Protein kinase C delta (PKCdelta), a Ca(2+)-independent, phospholipid-dependent serine/threonine kinase, is among the novel PKCs (delta, epsilon, and eta) expressed in mouse epidermis [13].
• We suggest that the effects of TNF-alpha on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCdelta and -alpha with upstream signaling molecules [20].
• Among the PKC inhibitors used only rottlerin, a selective inhibitor of PKCdelta, markedly inhibited the UVB-induced activation of Erks and JNKs, but not p38 kinases [14].
• PKCdelta was activated by arsenate treatment by in vitro kinase assays [15].
• In contrast, activation of the c-Jun amino-terminal kinase is reduced in primary parotid cells from PKCdelta(-/-) cells and in parotid C5 cells, which express a dominant inhibitory mutant of PKCdelta [18].
• The inhibitor of PKCdelta kinase activity rottlerin blocks the translocation of the PKCdelta-Abl complex from the ER to the mitochondria and confers protection against apoptosis [21].

Physical interactions of Prkcd

• Immunoprecipitation revealed that p53 co-immunoprecipitated with PKC-delta and was phosphorylated at the 15th serine residue in SNP-treated cells [22].
• HSP25 binds to kinase-active PKCdelta to inhibit its kinase activity and translocation to the membrane, which results in reduced cell death [23].
• In addition, a fraction of PKC-delta and -eta appears membrane-bound and concentrated in the Golgi apparatus [24].
• West-Western screening of a cDNA expression library using 32P-labeled, autophosphorylated protein kinase Cdelta (PKCdelta) as a probe, led us to identify cDNA clones encoding a PKCdelta-binding protein that contains a leucine zipper-like motif in its N-terminal region and two PEST sequences in its C-terminal region [25].

Enzymatic interactions of Prkcd

• PKCdelta (deltaI) is proteolytically cleaved at its hinge region (V3) by caspase 3 and the catalytic fragment is sufficient to induce apoptosis in various cell types [26].
• The structural requirements of PKC were then examined using a calpain-cleaved active fragment of nPKC delta [27].
• The PKCdelta that was tyrosine-phosphorylated in response to TGFalpha had reduced activity compared with the nontyrosine-phosphorylated PKCdelta [28].
• An in vitro kinase assay revealed that p53 was directly phosphorylated by SNP-activated PKC-delta [22].

Regulatory relationships of Prkcd

• Further, overexpression of PKCdelta inhibited growth of cells expressing wild-type Kit and enhanced growth of cells expressing the Kit mutant [29].
• Pretreatment of macrophages with PKCdelta-specific inhibitor rottlerin prior to the UV-B irradiation inhibits activation of caspase-3, PARP cleavage, DNA fragmentation and release of intracellular Ca2+ [30].
• Our data suggest the existence of a previously unknown BAFF-induced and PKCdelta-mediated nuclear signalling pathway which regulates B-cell survival [31].
• These results demonstrated that PKCdelta overexpression enhanced radiation-induced apoptosis and radiosensitivity via ERK1/2 activation, thereby abolishing the radiation-induced G(2)-M arrest and finally apoptosis [32].
• This suggests that TGFalpha-induced tyrosine phosphorylation of PKC delta results from the activation of a tyrosine kinase rather than physical association of PKCdelta with a membrane-anchored tyrosine kinase [28].

Other interactions of Prkcd

• Here we investigate the role of protein kinase Cdelta (PKCdelta) in responses mediated by wild-type murine Kit and the D814Y mutant in a murine mast cell-like line [29].
• Our results identify PKCdelta and MEK-1 as essential, positive regulators of GLI-mediated HH signaling [33].
• The inhibition of PKCdelta by rottlerin did not affect the activation of p38 MAPK by arsenate [15].
• These studies indicate an essential role for PKCdelta downstream of the p53 response and upstream of the c-Jun amino-terminal kinase activation in DNA damage-induced apoptosis in vivo and in vitro [18].
• Our results suggested that activation of PKCdelta and PKCepsilon provide a negative regulation for Akt phosphorylation and kinase activity in mouse keratinocytes and serve as modulators of cell survival pathways in response to external stimuli [16].

Analytical, diagnostic and therapeutic context of Prkcd

• Western blot analysis of the amounts of protein kinase C alpha (PKC alpha) and PKC delta in the soluble fraction and the Triton X-100-soluble particulate fraction revealed that translocation of both isozymes from the soluble to the particulate fraction was reversible when the phorbol esters were washed off [34].
• To determine the domain of PKC-delta that is responsible for this isotype-specific function, cDNAs that encode reciprocal chimeras of PKC-delta and -epsilon (PKC-delta epsilon and PKC-epsilon delta) were constructed by exchanging regulatory and kinase domains using polymerase chain reaction technology [35].
• Microarray analysis indicated significant changes in expression levels between B6 and 129 mice in the identified chromosomal area of Wnt5a and protein kinase Cdelta (PKCdelta) [36].
• PKC-delta levels are significantly higher in Tam-resistant tumors compared to Tam-sensitive tumors in xenograft model (P<0.05) [37].
• Confocal microscopy analysis of LTXBO oocytes during this transition showed PKC-delta associated with the meiotic spindle and then with the chromosomes at MII [38].

References