Loss of the cylindromatosis tumor suppressor inhibits apoptosis by activating NF-kB

Speaker： 許 聿 翹                    Commentator： 賴 明 德  老師

Date： Oct. 8, 2003; 14：00~15：00 （Room 601）

Abstract：

    The family of de-ubiquitinating enzymes (DUBs) consists of ubiquitin carboxy-terminal hydrolases and ubiquitin-specific processing proteases. To study this gene family, the authors designed a collection of RNA interference vectors to suppress 50 human DUB enzymes. They identified that inhibition of one of these enzymes, the familial cylindormatosis tumor suppressor gene (CYLD), enhances activation of the transcription factor KF-kB. Mutations on CYLD result in the disease familial cylindromatosis, an autosomal dominant genetic predisposition to multiple tumors of the skin appendages¹. TNF receptor-associated factors (TRAFs) are involved in cytokine-mediated activation of NF-kB. The authors showed that the effect of CYLD on NF-kB activation is mediated by CYLD-dependent de-ubiquitination of TRAF2. CYLD binds to NEMO (NF-kB essential modulator), also known as IKKg, component of the IkB kinase (IKK) complex, and appears to regulate its activity through de-ubiquitination of TRAF2². The pro-apoptotic activity of TNF-a can be inhibited by activation of NF-kB, which activates a number of anti-apoptotic genes. The authors found that inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. Both sodium salicylate (an aspirin derivative) and prostaglandin A1 (PGA1) can inhibit NF-kB through inhibition of IKKb, ³ the kinase which is hyper-activated as a result of CYLD knockdown. These results suggest a therapeutic intervention strategy to restore growth control in patients suffering from

familial cylindromatosis.

References：

1.      Bignell, G. R. et al. (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nature Genet. 25,160–165.

2.      Brummelkamp, T. R., Nijman, S. M., Dirac, A. M., Bernards, R. (2003) Loss of the cylindromatosis tumor suppressor inhibits apoptosis by activating NF-kB. Nature 424, 797-801.

3.      Yin, M. J., Yamamoto, Y., Gaynor, R. B. (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of IkB kinase-b. Nature 396, 77–80.