MAPK‐dependent expression of p21<sup>WAF</sup> and p27<sup>kip1</sup> in PMA‐induced differentiation of HL60 cells

Das, Dipak K.; Pintucci, Giuseppe; Stern, Arnold

doi:10.1016/s0014-5793(00)01416-2

Cited by 96 publications

(68 citation statements)

References 11 publications

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“…This finding was in accordance with our previous work (Zhu et al, 2000) and several other studies (Zeng and el-Deiry, 1996;Das et al, 2000;Sugibayashi et al, 2001). Studies suggest that PKC activates the MEK-ERK pathway in a Raf-dependent manner (Kolch et al, 1993), Raf-1/ MEK/ERK pathway also regulates expression of the p21 waf1/cip1 gene (Beier et al, 1999).…”

Section: Discussionsupporting

confidence: 92%

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

et al. 2002

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Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-b 1 , increased the expression of PKCd and PKCZ, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE 2 receptor antagonists could not reverse the inhibition effect on PKCb 1 by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCb 1 attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21 waf1/cip1 . Inhibition of PKCb 1 -mediated overexpression of p21 waf1/cip1 partially reduced the anti-apoptotic effect of PKCb 1 . The down-regulation of PKCb 1 provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCb 1 act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.

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Section: Discussionsupporting

confidence: 92%

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

et al. 2002

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“…For example, PKC inhibitor staurosporine inhibited TPA-induced p21 WAF1/CIP1 protein expression (Zeng and El-Deiry, 1996), and PMA-induced p21 WAF1/CIP1 upregulation is involved in integrating PKC or MAP kinase pathways (Barboule et al, 1999;Das et al, 2000). TPA is a wellcharacterized activator of PKC.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of p21WAF1/CIP1 leads to morphologic changes and esterase activity in TPA-mediated differentiation of human prostate cancer cell line TSU-Pr1

et al. 2001

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We reported previously that human prostate cancer cell line TSU-Pr1 can di erentiate into microglia-like cells by 12-O-tetra-decanoylphorbol-13-acetate (TPA) treatment. In this study, we identi®ed a signal transduction pathway involved in TPA-induced TSU-Pr1 cell di erentiation and investigated the mechanism of growth arrest that accompanies this di erentiation. TPAinduced di erentiation and growth arrest of TSU-Pr1 cells were inhibited by treatment with Protein kinase C (PKC) inhibitor GF109203X and mitogen-activated protein (MAP) kinase inhibitor PD98059. Treatment of TSU-Pr1 cells with TPA for 15 min or longer resulted in translocation of PKCa, PKCg, and PKCe from cytosolic to membrane fraction. Our results suggest that TPAinduced TSU-Pr1 cell di erentiation is associated with activation of MAP kinase and PKCa, PKCg, and PKCe. The mechanism of growth arrest in TSU-Pr1 cells that underwent TPA-induced di erentiation were examined for factors in the signaling pathway downstream of MAP kinase that control the cell cycle. Upregulation of p21 WAF1/CIP1 cyclin-dependent kinase inhibitor protein was observed in a manner dependent on PKC or MAP kinase. Moreover, adenovirus-mediated overexpression of recombinant p21 WAF1/CIP1 in TSU-Pr1 cells result in growth arrest, morphological change to microglia-like cells, and increased a-naphthyl acetate esterase activity, all of which are associated with cellular di erentiation. Thus, our results indicate that p21 WAF1/CIP1 mediates TPA-induced growth arrest and di erentiation of TSUPr1 cells. Oncogene (2001) 20, 1220 ± 1228.

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“…Inhibition of ERK signaling was achieved using either 10 M U0126 or 50 M PD098059 (inhibitors that block the ability of MEK1 and MEK2 to phosphorylate/activate downstream targets (29 -31)). Cells were treated with inhibitors or vehicle at various times either prior to (30 min), at the same time, or after (30,45,60,75,90,105,120,135, and/or 150 min) the addition of PKC agonists and were maintained in the medium for the duration of PKC agonist treatment.…”

Section: Methodsmentioning

confidence: 99%

Involvement of the ERK Signaling Cascade in Protein Kinase C-mediated Cell Cycle Arrest in Intestinal Epithelial Cells

Clark¹,

Black²,

Leontieva

et al. 2004

Journal of Biological Chemistry

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Waf1/Cip1 induction, and cell cycle arrest. PKCinduced ERK activation was strong and sustained relative to that produced by proliferative signals, and the growth inhibitory effects of PKC agonists were dominant over proliferative events when these opposing stimuli were administered simultaneously. PKC signaling promoted cytoplasmic and nuclear accumulation of ERK activity, whereas growth factor-induced phospho-ERK was localized only in the cytoplasm. Comparison of the effects of PKC agonists that differ in their ability to sustain PKC ␣ activation and growth arrest in IEC-18 cells, together with the use of selective kinase inhibitors, indicated that the length of PKC-mediated cell cycle exit is dictated by the magnitude/duration of input signal (i.e. PKC ␣ activity) and of activation of the ERK cascade. The extent/duration of phospho-ERK nuclear localization may also be important determinants of the duration of PKC agonist-induced growth arrest in this system. Taken together, the data point to PKC ␣ and the Ras/Raf/MEK/ERK cascade as key regulators of cell cycle withdrawal in intestinal epithelial cells.

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MAPK‐dependent expression of p21^WAF and p27^kip1 in PMA‐induced differentiation of HL60 cells

Cited by 96 publications

References 11 publications

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Upregulation of p21WAF1/CIP1 leads to morphologic changes and esterase activity in TPA-mediated differentiation of human prostate cancer cell line TSU-Pr1

Involvement of the ERK Signaling Cascade in Protein Kinase C-mediated Cell Cycle Arrest in Intestinal Epithelial Cells

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MAPK‐dependent expression of p21WAF and p27kip1 in PMA‐induced differentiation of HL60 cells

Cited by 96 publications

References 11 publications

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Upregulation of p21WAF1/CIP1 leads to morphologic changes and esterase activity in TPA-mediated differentiation of human prostate cancer cell line TSU-Pr1

Involvement of the ERK Signaling Cascade in Protein Kinase C-mediated Cell Cycle Arrest in Intestinal Epithelial Cells

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MAPK‐dependent expression of p21^WAF and p27^kip1 in PMA‐induced differentiation of HL60 cells