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 ( 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 model of colonial growth.