Journal article
Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIPL and MKP-1, thereby antagonizing UV-induced apoptosis
Cell death and differentiation, Vol.15(10), pp.1654-1662
06/20/2008
DOI: 10.1038/cdd.2008.87
PMID: 18566605
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)-α-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-FLIPL) and mitogen-activated protein kinase phosphatase-1 (MKP-1), but not DLC and p21WAF1 by CREB was required for cAMP-mediated inhibition of JNK activation. The suppression by cAMP of UV-induced apoptosis was reversed by c-FLIPL 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.
Details
- Title: Subtitle
- Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIPL and MKP-1, thereby antagonizing UV-induced apoptosis
- Creators
- J Zhang - University of Iowa, PathologyQ WangN ZhuM Yu - Academy of Military Medical SciencesB Shen - Academy of Military Medical SciencesJ Xiang - University of Iowa, Internal MedicineA Lin
- Resource Type
- Journal article
- Publication Details
- Cell death and differentiation, Vol.15(10), pp.1654-1662
- DOI
- 10.1038/cdd.2008.87
- PMID
- 18566605
- ISSN
- 1350-9047
- eISSN
- 1476-5403
- Language
- English
- Date published
- 06/20/2008
- Academic Unit
- Pathology
- Record Identifier
- 9984195953202771
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