Abstract
Cold shock proteins are up-regulated by cellular stress and orchestrate inflammatory responses, cell proliferation, and differentiation. Enhanced cold shock protein expression promotes malignant cell transformation; up-regulation is detected in most cancers and associated with poor prognosis. Akt1, a serine/threonine kinase, is a potent oncogene, which activates pro-proliferative and anti-apoptotic signaling pathways, and phosphorylates the cold shock domain. Unexpectedly, chicken-YB-1 abrogates PI3K-Akt-dependent oncogenic cell transformation in embryonic fibroblasts. Here, we addressed the question whether chicken and human Y-box binding protein-1 (YB-1) act differently on cell transformation, and how a related protein, DNA-binding protein-A (DbpA) behaves in comparison. NIH3T3 cells were transduced with lentiviral vectors encoding for myristoylated (constitutive active) Akt1, YB-1, DbpA, or shRNA targeting YB-1 expression. Colony formation assays showed that human YB-1 acts similar to chicken on Akt-dependent cell transformation. This activity was not titratable. Given the correlation of nuclear YB-1 and upregulated DbpA expression in a series of clear cell renal cell carcinomas (n = 40) the colony formation assay was extended to include ectopic DbpA expression. DbpA alone prominently induced cell transformation, which was enhanced when constitutive active Akt1 or concomitant YB-1 expression was present. Notably, co-expression of DbpA together with YB-1 abrogated the repressive effect on Akt1 signaling observed with YB-1 alone. Macroscopically, some colonies yielded a remarkable “invasive” phenotype. Thus, cold shock proteins may convey profound anti- and pro-oncogenic effects on Akt-dependent cell transformation. DbpA is able to overcome the anti-oncogenic effects seen with combined YB-1 and Akt signaling in an in vitro model of colonial growth.
Highlights
Cold shock proteins (CSPs) are among the most evolutionarily conserved proteins
To test the primary question how human (h) Y-box binding protein-1 (YB-1) and chickenYB-1 influence malignant cell transformation mediated by Akt1 signaling, we first set up experiments similar to Bader et al [30] and tested their ability to propagate or prevent anchorage-independent growth
Since protein family members are involved in the regulation of transcription and translation, pre-mRNA splicing, cell cycle progression, DNA repair, nucleo-cytoplasmic cargo of proteins, their repertoire of functions is broad and may be involved in all levels of carcinogenesis
Summary
Cold shock proteins (CSPs) are among the most evolutionarily conserved proteins. This protein family is characterized by the presence of one or more cold shock domains, which possess nucleic acid binding properties.This endows these proteins with pleiotropic functions, such as the regulation of transcription, translation, and cell proliferation [1].In humans, the predominant group of cold shock domain proteins is the Y-box family. Cold shock proteins (CSPs) are among the most evolutionarily conserved proteins This protein family is characterized by the presence of one or more cold shock domains, which possess nucleic acid binding properties. This endows these proteins with pleiotropic functions, such as the regulation of transcription, translation, and cell proliferation [1]. The predominant group of cold shock domain proteins is the Y-box family. The prototypic member is Y-box binding protein 1 (YB-1), known www.oncotarget.com as DNA binding protein B (DbpB), encoded by the gene Ybx. DNA binding protein A (DbpA) and C (DbpC), are encoded by the genes Ybx and Ybx, respectively
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