title: IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs.
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 TNFalpha, vinblastine, etoposide and gamma-radiation. In contrast, IG20 expression suppressed cell replication and increased susceptibility to the above treatments. Moreover, cells that were resistant and susceptible to TNFalpha-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 TNFalpha, TRAIL and gamma-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 NFkappaB 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.
authors.affiliation: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Efimova
authors.forename: Adeeb M
authors.initials: AM
authors.lastname: Al-Zoubi
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Martinez
authors.forename: Shashi
authors.initials: S
authors.lastname: Kaithamana
authors.forename: Shenfeng
authors.initials: S
authors.lastname: Lu
authors.forename: Takayasu
authors.initials: T
authors.lastname: Arima
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
mesh_terms: D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053418:Death Domain Receptor Signaling Adaptor Proteins; D005786:Gene Expression Regulation; D014644:Genetic Variation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D020672:I-kappa B Proteins; C105852:MADD protein, human; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha