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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

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Abstract

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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Abbreviations

PKC:

Protein kinase C

PMA:

Phorbol 12-myristate 13-acetate

ASK1:

Apoptosis signal-regulating kinase 1

WT:

Wild-type

DN:

Dominant negative

CA:

Constitutively active

MBP:

Myelin basic protein

CHX:

Cycloheximide

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

RT-PCR:

Reverse transcriptase-polymerase chain reaction

siRNA:

Small interfering RNA

TNF:

Tumor necrosis factor

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

JNK:

c-jun N-terminal kinase

ERK1/2:

Extracellular signal-regulated kinase1/2

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0000100), by MOEHRD (KRF-2008-532-E00007), by the Infection Signaling Network Research Center (R13-2007-020-01002-0) at Chungnam National University, and a grant from the National R&D Program for Cancer Control Ministry of Health & Welfare, Republic of Korea (No: 0720560). We thank Timothy A Hoffman and Ji Hoon Lee for assistance in the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, Daejeon Regional Cancer Center, College of Medicine, Chungnam National University, Daejeon, 301-131, Republic of Korea

    Young-Rae Kim, Hee Sun Byun, Juhee Jeon, Byung Lyul Choi, Kyeong Ah Park, Minho Won, Tiejun Zhang, Sanghee Shin, Hyunji Lee & Gang Min Hur

  2. Laboratory of Cellular Oncology, Korea University Graduate School of Medicine, Ansan, Gyeonggi do, 425-707, Republic of Korea

    Junseo Oh

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  1. Young-Rae Kim
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Correspondence to Gang Min Hur.

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Young-Rae Kim and Hee Sun Byun are co-first authors.

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Kim, YR., Byun, H.S., Jeon, J. et al. Apoptosis Signal-Regulating Kinase1 is Inducible by Protein Kinase Cδ and Contributes to Phorbol Ester-Mediated G1 Phase Arrest Through Persistent JNK Activation. Cell Biochem Biophys 61, 199–207 (2011). https://doi.org/10.1007/s12013-011-9189-1

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