Role of Protein Kinase C (PKC) in Short- and Long-Term Cellular Responses

ABSTRACT The tumor suppressor p53 eliminates cancer-prone cells via multiple mechanisms, including apoptosis. Ras elicits apoptosis in cells after protein kinase C (PKC) downregulation. However, the role of p53 in Ras-mediated apoptosis has not been fully investigated. Here, we demonstrate that mouse fibroblasts that express wild-type p53 are more susceptible to apoptosis elicited by PKC inhibition if Ras is transiently expressed or upregulated as opposed to stably expressed. In the latter case, p53 is frequently mutated. Transiently increased Ras activity induces Bax, and PKC inhibition augments this induction. Overexpression of E6 inactivates p53 and thereby suppresses both Bax induction and apoptosis. In contrast, Bax is not induced in stable ras transfectants, regardless of PKC inhibition. The data suggest that short- and long-term activation of Ras use a different mechanism(s) to initiate apoptosis. The status of p53 may contribute to such differences.

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Long-term modulation of mitochondrial Ca2+ signals by protein kinase C isozymes

The Journal of Cell Biology ◽

10.1083/jcb.200311061 ◽

2004 ◽

Vol 165 (2) ◽

pp. 223-232 ◽

Cited By ~ 61

Author(s):

Paolo Pinton ◽

Sara Leo ◽

Mariusz R. Wieckowski ◽

Giulietta Di Benedetto ◽

Rosario Rizzuto

Keyword(s):

Protein Kinase C ◽

Insulin Secretion ◽

Protein Kinase ◽

Regulatory Mechanism ◽

Cellular Responses ◽

Kinase C ◽

A Cell ◽

Dynamic Interplay

The modulation of Ca2+ signaling patterns during repetitive stimulations represents an important mechanism for integrating through time the inputs received by a cell. By either overexpressing the isoforms of protein kinase C (PKC) or inhibiting them with specific blockers, we investigated the role of this family of proteins in regulating the dynamic interplay of the intracellular Ca2+ pools. The effects of the different isoforms spanned from the reduction of ER Ca2+ release (PKCα) to the increase or reduction of mitochondrial Ca2+ uptake (PKCζ and PKCβ/PKCδ, respectively). This PKC-dependent regulatory mechanism underlies the process of mitochondrial Ca2+ desensitization, which in turn modulates cellular responses (e.g., insulin secretion). These results demonstrate that organelle Ca2+ homeostasis (and in particular mitochondrial processing of Ca2+ signals) is tuned through the wide molecular repertoire of intracellular Ca2+ transducers.

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The role of PKMζ in the maintenance of long-term memory: a review

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0105 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Hamish Patel ◽

Reza Zamani

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Long Term Potentiation ◽

Global Memory ◽

Long Term Memory ◽

Compensatory Mechanism ◽

Term Memory ◽

Kinase C

Abstract Long-term memories are thought to be stored in neurones and synapses that undergo physical changes, such as long-term potentiation (LTP), and these changes can be maintained for long periods of time. A candidate enzyme for the maintenance of LTP is protein kinase M zeta (PKMζ), a constitutively active protein kinase C isoform that is elevated during LTP and long-term memory maintenance. This paper reviews the evidence and controversies surrounding the role of PKMζ in the maintenance of long-term memory. PKMζ maintains synaptic potentiation by preventing AMPA receptor endocytosis and promoting stabilisation of dendritic spine growth. Inhibition of PKMζ, with zeta-inhibitory peptide (ZIP), can reverse LTP and impair established long-term memories. However, a deficit of memory retrieval cannot be ruled out. Furthermore, ZIP, and in high enough doses the control peptide scrambled ZIP, was recently shown to be neurotoxic, which may explain some of the effects of ZIP on memory impairment. PKMζ knockout mice show normal learning and memory. However, this is likely due to compensation by protein-kinase C iota/lambda (PKCι/λ), which is normally responsible for induction of LTP. It is not clear how, or if, this compensatory mechanism is activated under normal conditions. Future research should utilise inducible PKMζ knockdown in adult rodents to investigate whether PKMζ maintains memory in specific parts of the brain, or if it represents a global memory maintenance molecule. These insights may inform future therapeutic targets for disorders of memory loss.

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Down-regulation of protein kinase C and kinase inhibitors dissociate short- and long-term enhancement produced by one-trial conditioning of Hermissenda

Journal of Neurophysiology ◽

10.1152/jn.1993.69.2.636 ◽

1993 ◽

Vol 69 (2) ◽

pp. 636-641 ◽

Cited By ~ 19

Author(s):

T. Crow ◽

J. Forrester

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Cellular Plasticity ◽

Short Term ◽

Down Regulation ◽

Kinase C ◽

Short And Long Term

1. The visual system of Hermissenda has been studied extensively as a site of cellular plasticity produced by classical conditioning. Previous research has shown that one-trial conditioning, consisting of light paired with serotonin (5-HT) results in short- and long-term enhancement of light-elicited generator potentials in identified type B-photoreceptors. Recent evidence suggests that 5-HT exerts its effects on the induction of short-term enhancement by activation of protein kinase C (PKC), a Ca(2+)-activated and phospholipid-dependent protein kinase. However, the contribution of protein kinases in general, and specifically PKC in long-term enhancement has not been established. 2. The protein kinase inhibitors H-7 and sphingosine blocked the induction of short-term enhancement when applied before one-trial conditioning. However, the conditions that are sufficient to block the induction of short-term enhancement do not block long-term enhancement. Sphingosine and H-7 do not block the induction and expression of long-term enhancement when applied before one-trial conditioning. 3. Pretreatment before conditioning with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which leads to down-regulation of PKC, also did not block long-term enhancement. Down-regulation by itself did not produce enhancement, although the transient peak of light-elicited generator potentials was reduced by pretreatment with TPA. 4. The results suggest that the induction of short- and long-term enhancement involve parallel processes, and thus the expression of long-term cellular plasticity produced by one-trial conditioning does not depend on the induction or expression of short-term enhancement.

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The role of protein kinase C in long-term potentiation: a testable model

Brain Research Reviews ◽

10.1016/0165-0173(89)90004-0 ◽

1989 ◽

Vol 14 (3) ◽

pp. 279-296 ◽

Cited By ~ 233

Author(s):

David J. Linden ◽

Aryeh Routtenberg

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Long Term Potentiation ◽

Kinase C ◽

Term Potentiation ◽

Testable Model

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Protein kinase C mechanisms that contribute to cardiac remodelling

Clinical Science ◽

10.1042/cs20160036 ◽

2016 ◽

Vol 130 (17) ◽

pp. 1499-1510 ◽

Cited By ~ 19

Author(s):

Alexandra C. Newton ◽

Corina E. Antal ◽

Susan F. Steinberg

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Protein Phosphorylation ◽

Cardiac Contractility ◽

Cellular Responses ◽

Growth Responses ◽

Kinase C ◽

Wide Range ◽

Clinical Disorders

Protein phosphorylation is a highly-regulated and reversible process that is precisely controlled by the actions of protein kinases and protein phosphatases. Factors that tip the balance of protein phosphorylation lead to changes in a wide range of cellular responses, including cell proliferation, differentiation and survival. The protein kinase C (PKC) family of serine/threonine kinases sits at nodal points in many signal transduction pathways; PKC enzymes have been the focus of considerable attention since they contribute to both normal physiological responses as well as maladaptive pathological responses that drive a wide range of clinical disorders. This review provides a background on the mechanisms that regulate individual PKC isoenzymes followed by a discussion of recent insights into their role in the pathogenesis of diseases such as cancer. We then provide an overview on the role of individual PKC isoenzymes in the regulation of cardiac contractility and pathophysiological growth responses, with a focus on the PKC-dependent mechanisms that regulate pump function and/or contribute to the pathogenesis of heart failure.

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