Molecular Mechanisms of Action of Gas1 and its Possible Therapeutic Applications

Gabriela      Dominguez-Monzon; Ricardo      Gonzalez-Ramirez; Jose      Segovia

Abstract

Growth Arrest Specific1 (Gas1) is a protein expressed during development and when cells arrest their growth. The potential of Gas1 as an adjuvant in the treatment of cancer, and its role as a tumor suppressor have also been proposed. We had previously demonstrated the structural relationship between Gas1 and the α receptors for the Glial-cell line-Derived Neurotrophic Factor (GDNF) family of ligands, and showed that Gas1 acts by inhibiting the intracellular signaling induced by GDNF, reducing both the pattern of autophosphorylation of Ret and the activation of AKT, thus inducing cell arrest and apoptosis. On the other hand, it has also been proposed that Gas1 positively interacts with Sonic Hedgehog (Shh) during embryonic development. In this review we will critically evaluate the data regarding the molecular mechanisms of action of Gas1, and discuss that the potential therapeutic effects of Gas1 treating cancer are related with its capacity inhibiting the intracellular signaling cascade induced by GDNF.

Keywords: Gas1, GDNF, Shh, Glioma, AKT, apoptosis, NIH-3T3 mouse cells, retrotransposon, chromosome 9q21.3-22.1., glycosil phosphatydilinositol, GFRs, NIH-3T3, lung adenocarcinoma, C6 murine glioma, U373 human glioma, primary cultures of human, cultures of hippocampal neurons, neuroblastoma, corpus luteum, methionine deprivation, chemopreventive agent (Green tea catechins), epirubicin, granule cells, Bergman glia fibers, microphthalmia, microform holoprosen-cephaly, multiple craniofacial defects, p53, Rb, B49 cells, neurturin (NRTN), artemin (ARTN), persephin (PSPN), tyrosine kinase, GFR1-4, GFR1, GFR2, GFR3, PSPN, Ret9, Ret43, Ret51, Shc, FRS2, DOK4/5, IRS1/2, enigma, MEN2A, familiar medullary thyroid carcinoma (FMTC), MEN2B, Yes-associate protein (YAP)