IG20, in contrast to DENN-SV, (MADD splice variants) suppresses tumor cell survival, and enhances their susceptibility to apoptosis and cancer drugs
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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DOI：
10.1038/sj.onc.1207210
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发表时间：
2004-02-05
期刊：
影响因子：
8
通讯作者：
Prabhakar, BS
中科院分区：
文献类型：
--
作者：
Efimova, EV;Al-Zoubi, AM;Prabhakar, BS
我们确定了人类IG20基因的7个可能的剪接变体。IG20、MADD、IG20- sv2和DENN-SV四种变异体在人体组织中表达。虽然DENN-SV在所有组织中组成性表达，但IG20的表达似乎受到调节。有趣的是，DENN-SV的过表达增强了细胞复制和对TNFalpha、长春花碱、etopo苷和γ辐射治疗的抗性。相反，IG20的表达抑制了细胞复制，增加了对上述处理的敏感性。此外，对tnfalpha诱导的凋亡具有抗性和易感的细胞分别只表达内源性DENN-SV和IG20。当缺乏内源性IG20变体，但表达更高水平的DENN-SV的PA-1卵巢癌细胞转染IG20时，它们表现出细胞增殖减少，对TNFalpha， TRAIL和γ辐射诱导的凋亡易感性增加。这表明IG20过表达可以覆盖内源性DENN-SV功能。CrmA能逆转IG20的作用，但不能逆转DENN-SV。相反，显性-负i -kappa B逆转了DENN-SV的作用，但不逆转IG20，这表明DENN-SV最有可能通过NFkappaB激活发挥作用。总之，我们的数据表明，IG20基因可以通过选择性mRNA剪接在调节细胞增殖、存活和死亡中发挥新的重要作用。
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.