Regulation of tumor suppressor PDCD4 by novel protein kinase C isoforms

Abstract

Transforming growth factor-beta1 (TGF-beta1) induces apoptosis in normal hepatocytes and hepatoma cells. PDCD4 is involved in TGF-beta1-induced apoptosis via the Smad pathway. The tumor promoter 12-O-tetradecanoylphorbor-13-acetate (TPA), a protein kinase C stimulator, inhibits TGF-beta1-induced apoptosis. However, the mechanisms of TPA action on PDCD4 expression remain to be elucidated. Therefore. the regulatory mechanism of PDCD4 expression by PKC was investigated. The treatment of the human hepatoma cell line, Huh7 with TPA suppressed PDCD4 protein expression and TGF-beta1 failed to increase the PDCD4 protein expression. PKC inhibitors Ro-31-8425 or bisindolylmaleimide-1-hydrocholoride (pan-PKC inhibitors) and rottlerin (PKCdelta inhibitor), but not Go6976 (PKCalpha inhibitor), enhanced the induction of PDCD4 protein by TGF-beta1. Furthermore, siRNA-mediated knockdown of PKCdelta and epsilon, but not PKCalpha, augmented the TGF-beta1-stimulated PDCD4 protein expression. However, TPA or pan-PKC inhibitor did not alter the PDCD4 mRNA expression either under basal- and TGF-beta1-treated conditions. The down-regulation of PDCD4 by TPA was restored by treatment with the proteasome inhibitor MG132. These data suggest that two isoforms of PKCs are involved in the regulation of the PDCD4 protein expression related to the proteasomal degradation pathway.

Expression patterns of the tumor suppressor PDCD4 and correlation with β-catenin expression in gastric cancers

“…21 and 22). The degradation of the protein was stimulated through activation of the Akt-mTOR-S6K signaling pathway and the MAP kinase pathway (11,12,14). It was reported that the PDCD4 protein and mRNA levels were often not correlated in human tumors (16,42).…”

“…Akt and ErK were also examined, because they function to control the PDCD4 levels by participating in the degradation of PDCD4 protein (11,12). Among them, only β-catenin expression was significantly correlated with PDCD4 expression (Fig.…”

“…Homologs in mice (MA-3/TIS) (4,5), chickens (6,7) and rats (DUG) (8) have also been reported. The expression of the gene is modulated by many factors, including interleukins (9), retinoid (10), 12-O-tetradecanoylphorbol 13 acetate (TPA) (11,12), transforming growth factor (TGF)-β1 (13), growth factors (14,15), topoisomerase inhibitors (5) and the transcription factor myb (6,7), and is up-regulated in association with apoptosis (4,13). PDCD4 expression has been shown to be suppressed in many tumor tissues, such as lung cancers (16), pancreatic cancers (17), hepatocellular carcinomas (13), colon cancers (18), skin carcinomas (15), breast cancers (19) and glioma tissues (20).…”

Enhanced Arginine Methylation of Programmed Cell Death 4 Protein during Nutrient Deprivation Promotes Tumor Cell Viability

“…Enhanced PDCD4 Protein Stability and Increased PRMT5 Activity Converge to Increase Methylated PDCD4 during Nutrient Deprivation-Several kinases, including S6K, Akt, and the PKC ␦ and ⑀ isoforms, have been shown to phosphorylate PDCD4 S67, targeting it for polyubiquitination and proteasomal degradation (21)(22)(23). To test whether methylated PDCD4 is subject to proteasomal degradation, MCF7 cells coexpressing PDCD4 and PRMT5 were treated with and without MG132 to block proteasomal degradation under normal growth, during HBSS treatment, and during recovery.…”

“…Phosphorylation by several kinases, including S6K, Akt, and PKC ␦ and ⑀, at serine 67 targets PDCD4 for proteasomal degradation (21)(22)(23), and, because overactivation of the PI3K-mTOR 5 signaling cascade is a common occurrence in tumors (24,25), this mechanism is thought to be the cause of down-regulation of PDCD4 in many tumors. PDCD4 levels have also been reported to decrease during the mitotic phase of the cell cycle, concomitant with other changes in the status of translational machinery (26).…”