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

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

“…However, IG20pa rendered cells highly susceptible to apoptosis induced by different death signals including TRAIL, and suppressed cell proliferation. In contrast, we had found that DENN-SV is overexpressed in tumor tissues and cancer cell lines, and expression of exogenous DENN-SV could confer resistance to apoptosis and enhance cell proliferation (Al-Zoubi et al, 2001;Efimova et al, 2003Efimova et al, , 2004Ramaswamy et al, 2004). These observations indicated that IG20-SVs could differentially regulate cell proliferation and death.…”

“…The IG20 gene plays an important role in cancer cell proliferation, apoptosis and survival Lee, 1996, 1998;Schievella et al, 1997;Brinkman et al, 1999;Murakami-Mori et al, 1999;Telliez et al, 2000;AlZoubi et al, 2001;Lim and Chow, 2002;Efimova et al, 2003Efimova et al, , 2004Lim et al, 2004;Ramaswamy et al, 2004). Additionally, it plays an important role in neurotransmission (Zhang et al, 1998;Tanaka et al, 2001;Yamaguchi et al, 2002), neurodegeneration (Del Villar and Miller, 2004) and guanine nucleotide exchange (Wada et al, 1997;Brown and Howe, 1998;Iwasaki and Toyonaga, 2000;Levivier et al, 2001).…”

“…Additionally, it plays an important role in neurotransmission (Zhang et al, 1998;Tanaka et al, 2001;Yamaguchi et al, 2002), neurodegeneration (Del Villar and Miller, 2004) and guanine nucleotide exchange (Wada et al, 1997;Brown and Howe, 1998;Iwasaki and Toyonaga, 2000;Levivier et al, 2001). These divergent functions are most likely mediated through alternative splicing (Chow et al, 1998;Al-Zoubi et al, 2001;Efimova et al, 2004).…”

Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines

“…Also the IG20 gene, which appears to have at least seven splice variants, encodes for a protein involved in the TNF-alpha signaling pathway; overexpression of its isoform DENN-SV, the only one expressed in normal brain, enhances cell replication and resistance to TNFalpha, vinblastine, etoposide and g-radiation, supporting the antiapoptotic and cell survival role of DENN-SV (Efimova et al, 2004).…”

Epidemiology and molecular pathology at crossroads to establish causation: molecular mechanisms of malignant transformation

“…One example is provided by IG20, a splice variant of MADD (MAP-K activating death domain-containing protein). IG20 is a protein interacting with the tumor necrosis factor alpha (TNFa) receptor (Al-Zoubi et al, 2001) and TNF-related apoptosis-inducing ligand) (TRAIL) receptor (Efimova et al, 2003). Through its activities, IG20 sensitizes the cell to apoptotic stimuli and induces the secretion of interleukin (IL)-6, thus suppressing tumor cell growth (BS Prabhakar, personal communication).…”