PKCη enhances cell cycle progression, the expression of G1 cyclins and p21 in MCF-7 cells

Abstract

Protein kinase C encodes a family of enzymes implicated in cellular di erentiation, growth control and tumor promotion. However, not much is known with respect to the molecular mechanisms that link protein kinase C to cell cycle control. Here we report that the expression of PKCZ in MCF-7 cells, under the control of a tetracycline-responsive inducible promoter, enhanced cell growth and a ected the cell cycle at several points. The induced expression of another PKC isoform, PKCd, in MCF-7 cells had opposite e ects and inhibited their growth. PKCZ expression activated cellular pathways in these cells that resulted in the increased expression of the G1 phase cyclins, cyclin D and cyclin E. Expression of the cyclin-dependent kinase inhibitor p21 WAF1 was also speci®cally elevated in PKCZ expressing cells, but its overall e ects were not inhibitory. Although, the protein levels of the cyclin-dependent kinase inhibitor p27 KIP1 were not altered by the induced expression of PKCZ, the cyclin E associated Cdk2 kinase activity was in correlation with the p27 KIP1 bound to the cyclin E complex and not by p21 WAF1 binding. PKCZ expression enhanced the removal of p27 KIP1 from this complex, and its re-association with the cyclin D/Cdk4 complex. Reduced binding of p27 KIP1 to the cyclin D/Cdk4 complex at early time points of the cell cycle also enhanced the activity of this complex, while at later time points the decrease in bound p21 WAF1 correlated with its increased activity in PKCZ-expressing cells. Thus, PKCZ induces altered expression of several cell cycle functions, which may contribute to its ability to a ect cell growth. Oncogene (2001) 20, 6794 ± 6804.

PKC-η mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways

“…The effects of PKC-Z on proliferation appear to be cell type specific. In this study using GBM cells, and another performed with epithelial breast adenocarcinoma MCF-7 cells (Fima et al, 2001), PKC-Z enhanced proliferation and cellcycle progression. However, studies using NIH3T3 cells and keratinocytes demonstrated inhibitory effects of PKC-Z on cell-cycle progression (Livneh et al, 1996;Ohba et al, 1998;Kashiwagi et al, 2000).…”

Ezrin-Radixin-Moesin Family Proteins Are Involved in Parvovirus Replication and Spreading

“…PKC was found to participate in multiple processes involved in cell proliferation (2,12), differentiation (16), survival, and death (1). It was shown that the activity of PKC is regulated by phosphorylation/dephosphorylation events, interaction with small molecules (diacylglycerol and acid lipids), and ubiquitin-dependent degradation (13).…”

Phorbol Ester-induced G1 Phase Arrest Selectively Mediated by Protein Kinase Cδ-dependent Induction of p21

“…Evidence accumulated in the last years points to distinct roles for individual PKC isozymes in the control of cell cycle progression, both at the levels of G 1 /S and G 2 /M transitions (2,3,28). Early studies in vascular endothelial cells have shown that phorbol esters potentiate the mitogenic effect of growth factors when added in early G 1 phase, but they inhibit DNA synthesis in late G 1 phase (22).…”

“…Phorbol esters, natural compounds that activate PKC and mimic the action of the lipid second messenger diacylglycerol, can impact on cell cycle progression both in positive or negative manners, resulting in either stimulation of mitogenesis or cell cycle arrest, or even in apoptosis, depending on the cell type (1)(2)(3)(4). Such a wide range of biological responses triggered by phorbol esters relates to the multiplicity of intracellular effectors for these compounds, which include the classic PKCs (␣, ␤I, ␤II, and ␥), the novel PKCs (␦, ⑀, , and ), as well as PKC-related kinases and nonkinase phorbol ester receptors (5,6).…”