IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs

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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 TNF, vinblastine, etoposide and -radiation. In contrast, IG20 expression suppressed cell replication and increased susceptibility to the above treatments. Moreover, cells that were resistant and susceptible to TNF-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 TNF, TRAIL and -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 NFB 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.