The Protein Kinase C (PKC) Family of Proteins in Cytokine Signaling in Hematopoiesis
The members of the protein kinase C (PKC) family of proteins play important roles in signaling for various growth factors, cytokines, and hormones. Extensive work over the years has led to the identification of three major groups of PKC isoforms. These include the classic PKCs (PKCalpha, PKCbeta(I), PKCbeta(II), PKCgamma), the novel PKCs (PKCdelta, PKCepsilon, PKCeta, PKCmu, PKCtheta), and the atypical PKCs (PKCzeta, PKCiota/lambda). All these PKC subtypes have been shown to participate in the generation of signals for important cellular processes and to mediate diverse and, in some cases, opposing biologic responses. There is emerging evidence that these kinases also play key functional roles in the regulation of cell growth, apoptosis, and differentiation of hematopoietic cells. In this review, both the engagement of the various PKC members in cytokine and growth factor signaling and their role in the regulation of hematopoiesis are discussed.
Available from: Stephany Corrêa
- "PKCs are subdivided into three classes that comprise different isoforms with particular features: 1) the classic PKCs (PKCα, PKCβI, PKCβII, PKCγ), which are Ca2+-dependent and activated by both PS and DAG; 2) the novel PKCs (PKCδ, PKCε, PKCη, PKCμ, PKCθ), which are only regulated by PS and DAG; and 3) atypical PKCs (PKCζ, PKCί/λ), which are Ca2+- and DAG-independent. These different classes are grouped according to protein-domain similarities and/or different activation signals (Figure 1).3 "
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ABSTRACT: Calcium-dependent protein kinases (PKCs) function in a myriad of cellular processes, including cell-cycle regulation, proliferation, hematopoietic stem cell differentiation, apoptosis, and malignant transformation. PKC inhibitors, when targeted to these pathways, have demonstrated efficacy against several types of solid tumors as well as leukemia. Chronic myeloid leukemia (CML) represents 20% of all adult leukemia. The aberrant Philadelphia chromosome has been reported as the main cause of CML development in hematopoietic stem cells, due to the formation of the BCR-ABL oncogene. PKCs and BCR-ABL coordinate several signaling pathways that are crucial to cellular malignant transformation. Experimental and clinical evidence suggests that pharmacological approaches using PKC inhibitors may be effective in the treatment of CML. This mini review summarizes articles from the National Center for Biotechnology Information website that have shown evidence of the involvement of PKC in CML.
Available from: Paula M Cannon
- "We observed significant enhancement of adenovirally delivered ZFN activity upon treatment with PMA and bryostatin. PKC is a serine/threonine kinase and is known to activate multiple intracellular signaling pathways in cells of the hematopoietic lineage.20 In order to investigate the mechanism of PKC-mediated enhancement of CCR5 gene disruption in HSPC, we analyzed the downstream activation of several intracellular signaling pathways known to be regulated by serine or threonine phosphorylation status. "
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ABSTRACT: The HIV-1 coreceptor CCR5 is a validated target for HIV/AIDS therapy. The apparent elimination of HIV-1 in a patient treated with an allogeneic stem cell transplant homozygous for a naturally occurring CCR5 deletion mutation (CCR5(Δ32/Δ32)) supports the concept that a single dose of HIV-resistant hematopoietic stem cells can provide disease protection. Given the low frequency of naturally occurring CCR5(Δ32/Δ32) donors, we reasoned that engineered autologous CD34(+) hematopoietic stem/progenitor cells (HSPCs) could be used for AIDS therapy. We evaluated disruption of CCR5 gene expression in HSPCs isolated from granulocyte colony-stimulating factor (CSF)-mobilized adult blood using a recombinant adenoviral vector encoding a CCR5-specific pair of zinc finger nucleases (CCR5-ZFN). Our results demonstrate that CCR5-ZFN RNA and protein expression from the adenoviral vector is enhanced by pretreatment of HSPC with protein kinase C (PKC) activators resulting in >25% CCR5 gene disruption and that activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway is responsible for this activity. Importantly, using an optimized dose of PKC activator and adenoviral vector we could generate CCR5-modified HSPCs which engraft in a humanized mouse model (albeit at a reduced level) and support multilineage differentiation in vitro and in vivo. Together, these data establish the basis for improved approaches exploiting adenoviral vector delivery in the modification of HSPCs.Molecular Therapy (2013); doi:10.1038/mt.2013.65.
Available from: Maurilio Sampaolesi
- "In the hematopoietic field, the role of PKCe has been demonstrated in the regulation of erythropoiesis and megakaryocytopoiesis (Mirandola et al. 2006; Gobbi et al. 2007; Redig and Platanias 2007). More recently, PKCe has been found implicated in colorectal cancer cell differentiation (Gobbi et al. 2012). "
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ABSTRACT: Protein kinase Cepsilon (PKCε) exerts a well-known cardio-protective activity in ischemia-reperfusion injury and plays a pivotal role in stem cell proliferation and differentiation. Although many studies have been performed on physiological and morphological effects of PKCε mis-expression in cardiomyocytes, molecular information on the role of PKCε on early cardiac gene expression are still lacking. We addressed the molecular role of PKCε in cardiac cells using mouse cardiomyocytes and rat bone marrow mesenchymal stem cells. We show that PKCε is modulated in cardiac differentiation producing an opposite regulation of the cardiac genes NK2 transcription factor related, locus 5 (nkx2.5) and GATA binding protein 4 (gata4) both in vivo and in vitro. Phospho-extracellular regulated mitogen-activated protein kinase 1/2 (p-ERK1/2) levels increase in PKCε over-expressing cells, while pkcε siRNAs produce a decrease in p-ERK1/2. Indeed, pharmacological inhibition of ERK1/2 rescues the expression levels of both nkx2.5 and gata4, suggesting that a reinforced (mitogen-activated protein kinase) MAPK signaling is at the basis of the observed inhibition of cardiac gene expression in the PKCε over-expressing hearts. We demonstrate that PKCε is critical for cardiac cell early gene expression evidencing that this protein is a regulator that has to be fine tuned in precursor cardiac cells.
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