Differential regulation of p53 function by protein kinase C isoforms revealed by a yeast cell system

Abstract

Edited by Varda RotterKeywords: p53 Protein kinase C isoform Cell growth Cell cycle p53 phosphorylation Yeast a b s t r a c tThe complexity of the mammalian p53 pathway and protein kinase C (PKC) family has hampered the discrimination of the effect of PKC isoforms on p53 activity. Using yeasts co-expressing the human wild-type p53 and a mammalian PKC-a, -d, -e or -f, we showed a differential regulation of p53 activity and phosphorylation state by PKC isoforms. Whereas PKC-a reduced the p53-induced yeast growth inhibition and cell cycle arrest, PKC-d and -e enhanced the p53 activity through p53 phosphorylation, and PKC-f had no effect on p53. This work identified positive and negative p53 regulators which represent promising pharmacological targets in anti-cancer therapy.

Protein Kinase Cα (PKCα) Regulates p53 Localization and Melanoma Cell Survival Downstream of Integrin αv in Three-dimensional Collagen and in Vivo

“…PKC␣ can phosphorylate the C-terminal region of p53 at Ser-376 and Ser-378 (16) and inhibit p53 in yeast (20), whereas PKC␣ overexpression promoted murine p53 transcriptional activity (17). The observed differences in the role of PKC␣ in p53 regulation could be a consequence of differences between the model systems used.…”

“…2C). PKC␣ can phosphorylate p53 in vitro (16), although its effect upon p53 activity remains unclear (17,20). Importantly, under three-dimensional collagen conditions, M21 (␣v ϩ ) cells with stably knocked down PKC␣ exhibited a reduced p53 relocalisation with a greater proportion of p53 within the nucleus compared with control M21 cells stably expressing GFP knockdown sequences (Fig.…”

“…PKC␣ can bind and phosphorylate the C terminus of p53 (16,17), although its effects upon p53 activity appear cell type specific (18,19). Meanwhile, a recent yeast model identified PKC␣ as an inhibitor of p53-induced growth arrest (20). Nevertheless, it has remained unclear how PKC␣ may be regulated and exert its role in malignant melanoma.…”

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

“…Other factors, which have been defined as regulators of p53 posttranslational modifications and activation, include Chk2 and ATM. 24,30,31 By using HCT116 Chk2 À / À cells and a specific inhibitor of ATM (KU55933), we could conclude that these factors did not contribute significantly to any of the 5-FU-induced p53 phosphorylation events analyzed. Still, in Chk2 À / À cells, processing of caspases-3 and -8 occurred at a slower rate compared with the parental cell line, implicating this factor in 5-FU-induced apoptosis by a yet unknown mechanism (Figure 6c).…”

“…Among kinase-dependent activity pathways acting on p53, only two are controlled by Ca 2 þ signaling. One of them involves serine/threonine kinase members included in a subgroup of the protein kinase C (PKC) family termed the classical group encompassing PKCs-a, -bI, -bII and -g. [24][25][26] The other one is facilitated by the ubiquitous Ca 2 þ -sensing protein CaM and occurs through activation of members contained in the superfamily of CaM-dependent kinases. [27][28][29] As a selective inhibitor of PKC (PKC412) did not attenuate p53 S15 phosphorylation in any of the concentrations tested, we concluded that this kinase did not contribute to the 5-FUinduced and Ca 2 þ -dependent events leading to p53 activity.…”