PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells

Yokoyama, Goro; Fujii, Teruhiko; Tayama, Kosuke; Yamana, Hideaki; Kuwano, Michihiko; Shirouzu, Kazuo

doi:10.1016/j.bbrc.2004.12.070

Cited by 24 publications

(16 citation statements)

References 42 publications

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“…To address the biological relevance of up-regulated ASK1 expression, the kinetics of MAPKs activation were assessed after PMA treatment. Being consistent with previous reports [18,19], the phosphorylation levels of JNK and ERK rapidly increased around 30 min and 1 h after PMA treatment (Fig. 3a), while there were marginal changes of p38 phosphorylation level at the same time point (data not shown).…”

Section: Up-regulated Ask1 Expression Contributes To the Pma-induced supporting

confidence: 93%

“…Because PMA-induced activation of PKC has been reported to mediate cell cycle arrest in breast cancer cells [11,18], we investigated whether the up-regulated ASK1 expression by PKCd is responsible for PMA-induced G1 arrest. To confirm the role of PKCd in the cell cycle regulation, the cell cycle distribution of MCF-7 cells overexpressed with wild-type (WT), dominant negative (DN, K376R), or constitutive active (CA, DNPS) mutants of PKCd was analyzed.…”

Section: Up-regulated Ask1 Expression Contributes To the Pma-induced mentioning

confidence: 99%

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Apoptosis Signal-Regulating Kinase1 is Inducible by Protein Kinase Cδ and Contributes to Phorbol Ester-Mediated G1 Phase Arrest Through Persistent JNK Activation

Kim

Byun

Jeon

et al. 2011

Cell Biochem Biophys

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Although protein kinase Cδ (PKCδ) has been suggested in the negative control of the cell cycle machinery in many types of cancer cells, its underlying mechanisms are partly understood. Here we report that the expression of apoptosis signal-regulating kinase1 (ASK1) is inducible in a PKCδ-dependent manner, and contributes to phorbol ester-induced cell cycle arrest through persistent JNK activation in breast cancer epithelial cells. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) gradually up-regulated the expression of ASK1 mRNA and protein, and subsequently enhanced its catalytic activity in MCF-7 cells. Importantly, such PMA-induced ASK1 expression was completely abolished by pretreatment of rottlerin, a specific PKCδ inhibitor or by knocking down the expression of PKCδ, while ectopic expression of a constitutively active form of PKCδ strongly up-regulated ASK1 expression. We also found that the persistent activation of mitogen-activated protein kinase, JNK in response to PMA was greatly attenuated by RNA interference-mediated knockdown of ASK1. Taken together, these results suggest that inducible expression of ASK1 by PKCδ contributes to the G1 arrest by enhancing persistent JNK signaling activation which represents a novel alternative mechanism of PKCδ-dependent cell cycle arrest and limiting proliferation of breast cancer epithelial cells.

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Section: Up-regulated Ask1 Expression Contributes To the Pma-induced supporting

confidence: 93%

Section: Up-regulated Ask1 Expression Contributes To the Pma-induced mentioning

confidence: 99%

Apoptosis Signal-Regulating Kinase1 is Inducible by Protein Kinase Cδ and Contributes to Phorbol Ester-Mediated G1 Phase Arrest Through Persistent JNK Activation

Kim

Byun

Jeon

et al. 2011

Cell Biochem Biophys

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“…Waf1 induction by phorbol esters (Zezula et al, 1997;Arita et al, 1998;Shanmugam et al, 2001;Nakagawa et al, 2005;Yokoyama et al, 2005). Although TPA is a general activator of phorbol ester sensitive PKC isoforms, we attribute these effects to PKC-d in these transfectants since the endogenous nontargeted PKC isoforms did not differ in expression in EV or PKC-d transfectants, compared to parental Caco-2 cells (Cerda et al, 2001).…”

Section: Kip2mentioning

confidence: 94%

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

et al. 2006

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PKC-d is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-d slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-d dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-d using a Zn 2 þ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-d caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, Po0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21 Waf1, a cyclin-dependent kinase (cdk) inhibitor in PKC-d transfectants compared with empty vector (EV) transfected cells, whereas the PKC-d specific inhibitor rottlerin (3 lM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21Waf1 expression. Concomitantly, compared to EV control cells, PKC-d upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-d increased binding of cdk inhibitor p27Kip1 to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-d plays in cell growth and cell cycle regulation, we knocked down PKC-d using specific siRNA oligonucleotides. PKC-d specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKCd protein by more than 80% in Caco-2 cells. Moreover, PKC-d knockdown enhanced cell proliferation (B1.4-2-fold, Po0.05) and concomitantly increased cyclin D1 and cyclin E expression (B1.7-fold, Po0.05). This was a specific effect, as nontargeted PKC-f was not changed by PKC-d siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-d transfectants, compared to EV cells, PKC-d upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-d specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-d regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-d that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-d in colonic carcinogenesis.

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“…The signal transduction kinetins regulated the expression of ARIP2 mRNA PMA is the activator of protein kinase C (PKC) [12] , A23187 is the calcium ion vector [13] , forskolin is the kinetin of cAMP-dependent protein kinase A (PKA) [14] and endotoxin LPS can bind with Toll-like receptor 4 on the surface of hepatocytes to stimulate cellular activities non-specifically [15] . To further study the regulation factors of ARIP2 expression, we used all of the above signal transduction activators to stimulate Hepal-6 cells and observed the expression of ARIP2 mRNA.…”

Section: Resultsmentioning

confidence: 99%

Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV

Zhou

Tai²,

Zhou³

et al. 2007

WJG

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AIM:To investigate the regulation of activin receptorinteracting protein 2 (ARIP2) expression and its possible relationships with collagen type Ⅳ (collagen Ⅳ) in mouse hepatoma cell line Hepal-6 cells. METHODS:The ARIP2 mRNA expression kinetics in Hepal-6 cells was detected by RT-PCR, and its regulation fa c t o r s w e re a n a l y ze d by t re a t m e n t w i t h s i g n a l transduction activators such as phorbol 12-myristate 13-acetate (PMA), forskolin and A23187. After pcDNA3-ARIP2 was transfected into Hepal-6 cells, the effects of ARIP2 overexpression on activin type Ⅱ receptor (ActRII) and collagen Ⅳ expression were evaluated. RESULTS:The expression levels of ARIP2 mRNA in Hapel-6 cells were elevated in time-dependent manner 12 h after treatment with activin A and endotoxin LPS, but not changed evidently in the early stage of stimulation (2 or 4 h). The ARIP2 mRNA expression was increased after stimulated with signal transduction activators such as PMA and forskolin in Hepal-6 cells, whereas decreased after treatment with A23187 (25.3% ± 5.7% vs 48.1% ± 3.6%, P < 0.01). ARIP2 overexpression could remarkably suppress the expression of ActRIIA mRNA in dose-dependent manner, but has no effect on ActRIIB in Hepal-6 cells induced by activin A. Furthermore, we have found that overexpression of ARIP2 could inhibit collagen Ⅳ mRNA and protein expressions induced by activin A in Hapel-6 cells. CONCLUSION:

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PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells

Cited by 24 publications

References 42 publications

Apoptosis Signal-Regulating Kinase1 is Inducible by Protein Kinase Cδ and Contributes to Phorbol Ester-Mediated G1 Phase Arrest Through Persistent JNK Activation

Apoptosis Signal-Regulating Kinase1 is Inducible by Protein Kinase Cδ and Contributes to Phorbol Ester-Mediated G1 Phase Arrest Through Persistent JNK Activation

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV

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