MAPK activating death domain (MADD) and DENN-SV are known to directly interact with TNFR1 cytoplasmic tail (Al-Zoubi AM et al. 2001). MADD and DENN-SV are two of at least six splice variants of IG20 gene. MADD and DENN-SV are constitutively expressed in all tissues and at much higher levels in cancer cells and tissues (Al-Zoubi AM et al. 2001; Lim KM et al. 2004). The expression of other IG20 isoforms, such as KIAA0358 and IG20-SV4, can be restricted to certain neuronal tissues (Li L et al. 2008). Regulation of expression of various splice variants can profoundly affect cancer cell survival, proliferation, or death (Efimova EV et al. 2004). Knockdown of IG20 using short hairpin RNA (shRNA) resulted in spontaneous apoptosis in HeLa (cervical cancer), PA-1 (ovarian carcinoma), WRO (follicular carcinoma) and FRO (anaplastic carcinoma) cells (Mulherkar N et al. 2006; Mulherkar N. et al. 2007; Subramanian M et al. 2009). MADD and DENN-SV have been shown to stimulate TNF-alpha and TRAIL-induced upregulation of prosurvival proteins suppressing caspase-8 activation (Kurada BR et al. 2009; Mulherkar N. et al. 2007; Subramanian M et al. 2009).