Essential requirement of apolipoprotein J (clusterin) signaling for IκB expression and regulation of NF-κB activity

被引:121
作者
Santilli, G
Aronow, BJ
Sala, A [1 ]
机构
[1] UCL, Inst Child Hlth, Mol Haematol & Canc Biol Unit, London WC1N 1EH, England
[2] Univ G DAnnunzio, Sez Oncol Med, Dipartimento Oncol & Neurosci, I-66100 Chieti, Italy
[3] Childrens Hosp, Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA
关键词
D O I
10.1074/jbc.C300252200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Apolipoprotein J/clusterin is an enigmatic protein highly regulated in inflammation, apoptosis, and cancer. Despite extensive studies, its biological function has remained obscure. Here we show that apolipoprotein J inhibits neuroblastoma cell invasion. Since this function can be regulated by NF-kappaB, we explored the possibility that apolipoprotein J might interfere with NF-kappaB signaling. Ectopic apolipoprotein J expression strongly inhibited NF-kappaB activity in human neuroblastoma cells and murine embryonic fibroblasts by stabilizing inhibitors of NF-kappaB (IkappaBs). Steady state levels of IkappaB proteins are drastically reduced in mouse embryo fibroblasts after disruption of the apolipoprotein J gene. Absence of apolipoprotein J causes reduction of IkappaB stability, a tumor necrosis factor-dependent increase in NF-kappaB activity, increased transcription of the NF-kappaB target gene c-IAP and down-modulation of p53 protein. These results suggest that an unexpected physiological role of apolipoprotein J is to inhibit NF-kappaB signaling through stabilization of IkappaBs and that this activity may result in suppression of tumor cell motility.
引用
收藏
页码:38214 / 38219
页数:6
相关论文
共 27 条
[1]   Downregulation of clusterin expression in testicular germ cell tumours [J].
Behrens, P ;
Jeske, W ;
Wernert, N ;
Wellmann, A .
PATHOBIOLOGY, 2001, 69 (01) :19-23
[2]   Activation of the nuclear factor-κB is a key event in brain tolerance [J].
Blondeau, N ;
Widmann, C ;
Lazdunski, M ;
Heurteaux, C .
JOURNAL OF NEUROSCIENCE, 2001, 21 (13) :4668-4677
[3]   Direct transactivation of the anti-apoptotic gene apolipoprotein J (Clusterin) by B-MYB [J].
Cervellera, M ;
Raschella, G ;
Santilli, G ;
Tanno, B ;
Ventura, A ;
Mancini, C ;
Sevignani, C ;
Calabretta, B ;
Sala, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (28) :21055-21060
[4]  
DiDonato J, 1996, MOL CELL BIOL, V16, P1295
[5]   A subclass of Ras proteins that regulate the degradation of IκB [J].
Fenwick, C ;
Na, SY ;
Voll, RE ;
Zhong, HH ;
Im, SY ;
Lee, JW ;
Ghosh, S .
SCIENCE, 2000, 287 (5454) :869-873
[6]  
Garg A, 2002, LEUKEMIA, V16, P1053, DOI 10.1038/sj.leu.2402482
[7]   Missing pieces in the NF-κB puzzle [J].
Ghosh, S ;
Karin, M .
CELL, 2002, 109 :S81-S96
[8]   Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia [J].
Han, BH ;
DeMattos, RB ;
Dugan, LL ;
Kim-Han, JS ;
Brendza, RP ;
Fryer, JD ;
Kierson, M ;
Cirrito, J ;
Quick, K ;
Harmony, JAK ;
Aronow, BJ ;
Holtzman, DM .
NATURE MEDICINE, 2001, 7 (03) :338-343
[9]   The IKK-2/IκBα/NF-κB pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts -: A critical link to dermatitis in IκBα-deficient mice [J].
Huber, MA ;
Denk, A ;
Peter, RU ;
Weber, L ;
Kraut, N ;
Wirth, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (02) :1268-1275
[10]   Clusterin [J].
Jones, SE ;
Jomary, C .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2002, 34 (05) :427-431