Protein kinase C signaling and cell cycle regulation

Abstract

A link between T cell proliferation and the protein kinase C (PKC) family of serine/threonine kinases has been recognized for about 30 years. However, despite the wealth of information on PKC-mediated control of, T cell activation, understanding of the effects of PKCs on the cell cycle machinery in this cell type remains limited. Studies in other systems have revealed important cell cycle-specific effects of PKC signaling that can either positively or negatively impact proliferation. The outcome of PKC activation is highly context-dependent, with the precise cell cycle target(s) and overall effects determined by the specific isozyme involved, the timing of PKC activation, the cell type, and the signaling environment. Although PKCs can regulate all stages of the cell cycle, they appear to predominantly affect G0/G1 and G2. PKCs can modulate multiple cell cycle regulatory molecules, including cyclins, cyclin-dependent kinases (cdks), cdk inhibitors and cdc25 phosphatases; however, evidence points to Cip/Kip cdk inhibitors and D-type cyclins as key mediators of PKC-regulated cell cycle-specific effects. Several PKC isozymes can target Cip/Kip proteins to control G0/G1 → S and/or G2 → M transit, while effects on D-type cyclins regulate entry into and progression through G1. Analysis of PKC signaling in T cells has largely focused on its roles in T cell activation; thus, observed cell cycle effects are mainly positive. A prominent role is emerging for PKCθ, with non-redundant functions of other isozymes also described. Additional evidence points to PKCδ as a negative regulator of the cell cycle in these cells. As in other cell types, context-dependent effects of individual isozymes have been noted in T cells, and Cip/Kip cdk inhibitors and D-type cyclins appear to be major PKC targets. Future studies are anticipated to take advantage of the similarities between these various systems to enhance understanding of PKC-mediated cell cycle regulation in T cells.

K562 cell proliferation is modulated by PLCβ1 through a PKCα-mediated pathway

“…[19][20][21] Several evidences indicate PKCs as key regulators of critical cell cycle phases, including G 0 -G 1 /S transition and G 2 /M progression. [16][17][18]22 Among them, PKCα, already reported to be part of PLCβ1 signaling, 11,13,23 is known for its involvement in G 1 /S transition. 24 It has been demonstrated that, in intestinal epithelial cells, an anti-proliferative regulation of Cyclin D1 was modulated by PKCα signaling.…”

“…As reported in the literature, PKCs are often involved in cell proliferation targeting key proteins of cell cycle regulation, such as cyclins, cyclin-dependent kinases and cyclin inhibitors like p21/Cip1 and p27/Kip1. 16,22,[30][31][32]40,41 The most expressed PKC isoforms in K562 cells are the conventional PKCα and PKCβII and the atypical PKCζ. 42 For this reason, we screened their levels in cells overexpressing PLCβ1 to evaluate if these PKC isoforms could be affected.…”

“…Several PKC isozymes are known to target D-type cyclins and regulate entry and progression through G 1 phase of the cell cycle. 16,17 Moreover, several papers showed that connections between PLCβ1 and PKCs are important in cell proliferation. 11,13 Then, we screened K562 to see which PKC isozymes were more expressed and, in accordance with the literature, 42 we decided to examine if the conventional isoforms PKCα and PKCβII and the atypical PKCζ could be modulated by PLCβ1.…”

“…[1][2][3]14,15 PKCs are serine/threonine kinases involved in the signal transduction in cellular proliferation and differentiation. [16][17][18] PKCs represent a family of 12 isozymes that have been categorized into three groups: group A, conventional or classical PKCs (cPKCs: α, βI, βII and γ); group B, novel PKCs (nPKCs: δ, ε, η and θ) and group C, or atypical PKCs (aPKCs: ζ and λ/ι). 19,20 This division in subclasses is due to the domain composition of the regulatory moiety.…”

CH Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation

“…However, while a variety of natural compounds activate PKCs, the outcome of PKC activation by a specific compound is highly context‐dependent, with the individual cellular targets (and off‐targets) and overall effects determined by the specific isozyme(s) involved, the timing of PKC activation, the cell type, and the signaling environment 5. This is reflected by comparing the biological activities of 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA), bryostatin 1, and ingenol mebutate ( 2 ): the first is a strong tumor promoter, the second shows antiproliferative properties, and latter has antitumoral properties and represents the active ingredient in Picato, a marketed product for the topical treatment of actinic keratosis (solar keratosis) 6…”