Guanine Nucleotide Binding Protein like-1 (GNL1) Promotes Cancer Cell Proliferation and Survival through AKT/p21CIP1 Signaling Cascade.

Human Guanine nucleotide binding protein like 1 (GNL1) is an evolutionary conserved putative nucleolar GTPase belonging to HSR1_MMR1 subfamily of GTPases. GNL1 was found to be highly upregulated in various cancers. Here, we report for the first time that GNL1 inhibits apoptosis by modulating the expression of Bcl2 family of proteins and the cleavage of caspases 7 and 8. Furthermore, GNL1 protects colon cancer cells from chemo-drug induced apoptosis. Interestingly, GNL1 upregulates the expression of p53 and its transcriptional target, p21 but the upregulation of p21 was found to be p53 dependent as well as independent mechanisms. Our results further demonstrate that GNL1 promotes cell growth and survival by inducing cytoplasmic retention and stabilization of p21 through AKT-mediated phosphorylation. In addition, GNL1 failed to inhibit apoptosis under p21 knockdown conditions suggest the critical role of p21 in GNL1 mediated cell survival. Finally, an inverse correlation of GNL1, p21 and AKT expression in primary colon and breast cancer with patient survival suggests their critical role in tumorigenesis. Collectively, our study reveals that GNL1 executes its anti-apoptotic function by a novel mechanism and suggests that it may functions as a regulatory component of the PI3K/AKT/p21 signaling network, to promote cell proliferation and survival in cancers.