Abstract
We identified seven putative splice variants of the human IG20 gene. Four variants namely, IG20, MADD, IG20-SV2 and DENN-SV are expressed in human tissues. While DENN-SV is constitutively expressed in all tissues, expression of IG20 appears to be regulated. Interestingly, overexpression of DENN-SV enhanced cell replication and resistance to treatments with TNFα, vinblastine, etoposide and γ-radiation. In contrast, IG20 expression suppressed cell replication and increased susceptibility to the above treatments. Moreover, cells that were resistant and susceptible to TNFα-induced apoptosis exclusively expressed endogenous DENN-SV and IG20, respectively. When PA-1 ovarian cancer cells that are devoid of endogenous IG20 variant, but express higher levels of DENN-SV, were transfected with IG20, they showed reduced cell proliferation and increased susceptibility to apoptosis induced by TNFα, TRAIL and γ-radiation. This indicated that overexpression of IG20 can override endogenous DENN-SV function. CrmA reversed the effects of IG20, but not DENN-SV. In contrast, dominant-negative-I-kappa B reversed the effects of DENN-SV, but not IG20, and showed that DENN-SV most likely exerted its effects through NFκB activation. Together, our data show that IG20 gene can play a novel and significant role in regulating cell proliferation, survival and death through alternative mRNA splicing.
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References
Al-Zoubi AM, Efimova EV, Kaithamana S, Martinez O, El-Idrissi ME, Dogan RE and Prabhakar BS . (2001). J. Biol. Chem., 276, 47202–47211.
Beg SS and Baltimore D . (1996). Science, 274, 782.
Breitbart RE, Andreadis A and Nadal-Ginard B . (1987). Ann. Rev. Biochem., 56, 467–495.
Brinkman BM, Telliez JB, Schievella AR, Lin LL and Goldfeld AE . (1999). J. Biol. Chem., 274, 30882–30886.
Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY and Ballard DW . (1995). Mol. Cell. Biol., 15, 2809–2818.
Brown TL and Howe PH . (1998). Curr. Biol., 8, R191.
Chinnaiyan AM, Tepper CG, Seldin MF, O'Rourke K, Kischkel FC, Hellbardt S, Krammer PH, Peter ME and Dixit VM . (1996). J. Biol. Chem., 271, 4961.
Chow VT and Lee SS . (1996). DNA Seq., 6, 263–273.
Chow VT, Lim KM and Lim D . (1998). Genome, 41, 543–552.
Cunningham SJ . (1996). Doctoral dissertation. The University of Texas Medical Branch, Graduate School of Biomedical Sciences at Galveston.
Goldstrohm AC, Greenleaf AL and Garcia-Blanco MA . (2001). Gene, 277, 31–47.
Goto Y, De Silva MG, Toscani A, Prabhakar BS, Notkins AL and Lan MS . (1992). J. Biol. Chem., 267, 15252–15257.
Herbert A and Rich A . (1999). Nat. Genet., 21, 265–269.
Hsu H, Huang J, Shu HB, Baichwal V and Goeddel DV . (1996a). Immunity, 4, 387.
Hsu H, Shu HB, Pan MG and Goeddel DV . (1996b). Cell, 84, 299.
Iwasaki K and Toyonaga R . (2000). EMBO J., 19, 4806–4816.
Jiang ZH and Wu JY . (1999). Proc. Soc. Exp. Biol. Med., 220, 64–72.
Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ and Leder P . (1998). Immunity, 8, 297.
Levivier E, Goud B, Souchet M, Calmels TP, Mornon JP and Callebaut I . (2001). Biochem. Biophys. Res. Commun., 287, 688–695.
Lim KM and Chow VT . (2002). Mol. Carcinog., 35, 110–126.
Lin Y, Devin A, Rodriguez Y and Liu ZG . (1999). Genes Dev., 13, 2514–2526.
Liu ZG, Hsu H, Goeddel DV and Karin M . (1996). Cell, 87, 565–576.
Malinin NL, Boldin MP, Kovalenko AV and Wallach D . (1997). Nature, 385, 540.
Martinon F, Holler N, Richard C and Tschopp J . (2000). FEBS Lett., 468, 134–136.
Murakami-Mori K, Mori S, Bonavida B and Nakamura S . (1999). J. Immunol., 162, 3672.
Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Miyajima N, Tanaka A, Kotani H, Nomura N and Ohara O . (1997). DNA Res., 4, 141–150.
Regnier CH, Song HY, Gao X, Goeddel DV, Cao Z and Rothe M . (1997). Cell, 90, 373.
Rothe M, Pan MG, Henzel WJ, Ayres TM and Goeddel DV . (1995). Cell, 83, 1243.
Schievella AR, Chen JH, Graham JR and Lin LL . (1997). J. Biol. Chem., 272, 12069–12075.
Sharp PA . (1994). Cell, 77, 805–815.
Smith CW and Valcarcel J . (2000). Trends Biochem. Sci., 25, 381–388.
Smrcka M, Horky M, Otevrel F, Kuchtickova S, Kotala V and Muzik J . (2003). Physiol. Res., 52, 117–122.
Telliez JB, Bean KM and Lin LL . (2000). Biochem. Biophys. Acta, 1478, 280–288.
Ting AT, Pimentel-Muinos FX and Seed B . (1996). EMBO J., 15, 6189.
Varfolomeev E, Boldin M, Goncharov T and Wallach D . (1996). J. Exp. Med., 183, 1271.
Wajant H, Pfizenmaier K and Scheurich P . (2002). Apoptosis, 7, 449–459.
Woronicz JD, Gao X, Cao Zd, Rothe M and Goeddel DV . (1997). Science, 278, 866.
Zhang Y, Zhou L and Miller CA . (1998). Proc. Natl. Acad. Sci. USA, 95, 2586–2591.
Acknowledgements
We thank the Kazusa Research Institute, Japan, for kindly providing a clone of human KIAA0358, and the Cooperative Human Tissue Network (CHTN), which is funded by the National Cancer Institute, for making available the human tissue samples. We also thank Drs Prasad Kanteti and Thomas Hope for their valuable critiques.
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Efimova, E., Al-Zoubi, A., Martinez, O. et al. IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs. Oncogene 23, 1076–1087 (2004). https://doi.org/10.1038/sj.onc.1207210
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DOI: https://doi.org/10.1038/sj.onc.1207210
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