We previously reported that a novel WD-40 domain-containing protein, p44/WDR77, drives quiescent epithelial cells to re-enter the cell cycle and plays an essential role for growth of lung and prostate cancer cells. Transforming growth factor beta (TGF beta) signaling is important in the maintenance of non-transformed cells in the quiescent or slowly cycling stage. However, both non-transformed proliferating cells and human cancer cells are non-responsive to endogenous TGF beta signaling. The mechanism by which proliferating cells become refractory to TGF beta inhibition is not well established. Here, we found that silencing p44/WDR77 increased cellular sensitivity to TGF beta signaling and that this was inversely correlated with decreased cell proliferation. Smad2 or 3 phosphorylation, TGF beta-mediated transcription, and TGF beta 2 and TGF beta receptor type II (T beta RII) expression were dramatically induced by silencing of p44/WDR77. These data support the hypothesis that p44/WDR77 down-regulates the expression of the TGF beta ligand and its receptor, thereby leading to a cellular non-response to TGF beta signaling. Finally, we found that p44/WDR77 expression was correlated with cell proliferation and decreased TGF beta signaling during lung tumorigenesis. Together, these results suggest that p44/WDR77 expression causes the nonsensitivity of proliferating cells to TGF beta signaling, thereby contributing to cellular proliferation during lung tumorigenesis. (C) 2014 Elsevier Inc. All rights reserved.