8.A.183.  The RelA-associated Inhibitor (RAI) Family 

RAI (Q9UKV5) is a regulator that plays a central role in the regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins in humans. It blocks transcription of HIV-1 virus by inhibiting the action of both NF-kappa-B and SP1. It also inhibits p53/TP53 function, possibly by preventing the association between p53/TP53 and ASPP1 or ASPP2, and therefore suppressing the subsequent activation of apoptosis (Bergamaschi et al. 2003). Other designations include: PPP1R13L, iASPP and NKIP1. iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca²⁺ homeostasis and control tumor growth and drug resistance (Zheng et al. 2022). 

Ca²⁺ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca²⁺ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca²⁺ homeostasis is linked with various cancer hallmarks.  Zheng et al. 2022 demonstrated that a reported Ca²⁺-channel protein TMCO1 (transmembrane and coiled-coil domains 1) (TC# 1.A.106.1.1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels. TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca²⁺ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between the iASPP and TMCO1 proteins has been validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca²⁺ overload-induced apoptotic cell death and reducing tumor growth both in vitro and in vivo (Zheng et al. 2022).