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Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIP(L) and MKP-1, thereby antagonizing UV-induced apoptosis.
Cell Death Differ. 2008 Oct; 15(10):1654-62.CD

Abstract

The cyclic AMP (cAMP) signaling pathway has been reported to either promote or suppress apoptosis, in a cell context-dependent manner. Our previous study has shown that cAMP, by protein kinase A (PKA)-cAMP response element-binding protein (CREB)-dynein light chain (DLC) pathway, negatively regulates mitogen-activated protein kinase p38 activation, thereby contributing to tumor necrosis factor (TNF)-alpha-induced apoptosis in certain types of cells. However, it remains largely unknown how cAMP suppresses apoptosis. Here we report that cAMP antagonized UV-induced apoptosis in Rat-1 and NIH 3T3 cells. Despite that cAMP significantly suppressed UV-induced p38 activation, inhibition of p38 activity showed no significant effect on UV-induced cell death in both cell lines. Further studies revealed that cAMP antagonized UV-induced apoptosis by inhibition of c-Jun N-terminal protein kinase (JNK) activation. The induction of the long form of cellular FLICE-inhibitory protein (c-FLIP(L)) and mitogen-activated protein kinase phosphatase-1 (MKP-1), but not DLC and p21(WAF1) by CREB was required for cAMP-mediated inhibition of JNK activation. The suppression by cAMP of UV-induced apoptosis was reversed by c-FLIP(L) small-interfering RNA (siRNA) or MKP-1 siRNA, which released the inhibition of JNK activation by cAMP. Thus, our results provide a molecular mechanism by which cAMP suppresses JNK activation and antagonizes apoptosis.

Authors+Show Affiliations

Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PR China. zhangjy@nic.bmi.ac.cnNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18566605

Citation

Zhang, J, et al. "Cyclic AMP Inhibits JNK Activation By CREB-mediated Induction of c-FLIP(L) and MKP-1, Thereby Antagonizing UV-induced Apoptosis." Cell Death and Differentiation, vol. 15, no. 10, 2008, pp. 1654-62.
Zhang J, Wang Q, Zhu N, et al. Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIP(L) and MKP-1, thereby antagonizing UV-induced apoptosis. Cell Death Differ. 2008;15(10):1654-62.
Zhang, J., Wang, Q., Zhu, N., Yu, M., Shen, B., Xiang, J., & Lin, A. (2008). Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIP(L) and MKP-1, thereby antagonizing UV-induced apoptosis. Cell Death and Differentiation, 15(10), 1654-62. https://doi.org/10.1038/cdd.2008.87
Zhang J, et al. Cyclic AMP Inhibits JNK Activation By CREB-mediated Induction of c-FLIP(L) and MKP-1, Thereby Antagonizing UV-induced Apoptosis. Cell Death Differ. 2008;15(10):1654-62. PubMed PMID: 18566605.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIP(L) and MKP-1, thereby antagonizing UV-induced apoptosis. AU - Zhang,J, AU - Wang,Q, AU - Zhu,N, AU - Yu,M, AU - Shen,B, AU - Xiang,J, AU - Lin,A, Y1 - 2008/06/20/ PY - 2008/6/21/pubmed PY - 2008/10/28/medline PY - 2008/6/21/entrez SP - 1654 EP - 62 JF - Cell death and differentiation JO - Cell Death Differ VL - 15 IS - 10 N2 - The cyclic AMP (cAMP) signaling pathway has been reported to either promote or suppress apoptosis, in a cell context-dependent manner. Our previous study has shown that cAMP, by protein kinase A (PKA)-cAMP response element-binding protein (CREB)-dynein light chain (DLC) pathway, negatively regulates mitogen-activated protein kinase p38 activation, thereby contributing to tumor necrosis factor (TNF)-alpha-induced apoptosis in certain types of cells. However, it remains largely unknown how cAMP suppresses apoptosis. Here we report that cAMP antagonized UV-induced apoptosis in Rat-1 and NIH 3T3 cells. Despite that cAMP significantly suppressed UV-induced p38 activation, inhibition of p38 activity showed no significant effect on UV-induced cell death in both cell lines. Further studies revealed that cAMP antagonized UV-induced apoptosis by inhibition of c-Jun N-terminal protein kinase (JNK) activation. The induction of the long form of cellular FLICE-inhibitory protein (c-FLIP(L)) and mitogen-activated protein kinase phosphatase-1 (MKP-1), but not DLC and p21(WAF1) by CREB was required for cAMP-mediated inhibition of JNK activation. The suppression by cAMP of UV-induced apoptosis was reversed by c-FLIP(L) small-interfering RNA (siRNA) or MKP-1 siRNA, which released the inhibition of JNK activation by cAMP. Thus, our results provide a molecular mechanism by which cAMP suppresses JNK activation and antagonizes apoptosis. SN - 1350-9047 UR - https://www.unboundmedicine.com/medline/citation/18566605/Cyclic_AMP_inhibits_JNK_activation_by_CREB_mediated_induction_of_c_FLIP_L__and_MKP_1_thereby_antagonizing_UV_induced_apoptosis_ L2 - https://doi.org/10.1038/cdd.2008.87 DB - PRIME DP - Unbound Medicine ER -