IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs.
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.
Efimova
Elena V
EV
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.
Al-Zoubi
Adeeb M
AM
Martinez
Osvaldo
O
Kaithamana
Shashi
S
Lu
Shenfeng
S
Arima
Takayasu
T
Prabhakar
Bellur S
BS
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
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