IKKß programs to turn on the GADD45–MKK4–JNK apoptotic cascade specifically via p50 NF-B in arsenite response

Lun Song¹, Jingxia Li¹, Dongyun Zhang¹, Zheng-gang Liu², Jianping Ye³, Qimin Zhan⁴, Han-Ming Shen⁵, Matt Whiteman⁶, , and Chuanshu Huang¹

¹ Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987
² Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
³ Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808
⁴ National Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, 100021, People's Republic of China
⁵ Department of Community, Occupational, and Family Medicine and ⁶ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore

Correspondence to Chuanshu Huang: chuanshu{at}env.med.nyu.edu

Abstract: Cross talk between NF-B and c-Jun N-terminal kinases (JNKs) has been implicated in the cell life and death decision under various stresses. Functional suppression of JNK activation by NF-B has recently been proposed as a key cellular survival mechanism and contributes to cancer cells escaping from apoptosis. We provide a novel scenario of the proapoptotic role of IB kinase ß (IKKß)–NF-B, which can act as the activator of the JNK pathway through the induction of GADD45 for triggering MKK4/JNK activation, in response to the stimulation of arsenite, a cancer therapeutic reagent. This effect of IKKß–NF-B is dependent on p50 but not the p65/relA NF-B subunit, which can increase the stability of GADD45 protein through suppressing its ubiquitination and proteasome-dependent degradation. IKKß–NF-B can therefore either activate or suppress the JNK cascade and consequently mediate pro- or antiapoptotic effects, depending on the manner of its induction. Furthermore, the NF-B p50 subunit can exert a novel regulatory function on protein modification independent of the classical NF-B transcriptional activity.

Abbreviations used in this paper: CHX, cyclohexamide; GADD, growth arrest and DNA damage inducible; IKK, IB kinase; MEF, mouse embryonic fibroblast; PARP, poly (ADP-ribose) polymerase; WT, wild-type.

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