PP-1α and PP-1γ Display Antagonism and Differential Roles in Tumorigenicity of Lung Cancer Cells

Z.-X.      Huang; D.      W.-C. Li; J.-P.      Liu; H.-G.      Chen; L.      Gong; M.      Deng; X.-H.      Hu; W.-F.      Hu; W.-K.      Ji; P.-C.      Chen; L.      Li; X.-W.      Chen; Z.-L.      Li; X.      Li; S.-J.      Fu; Z.-W.      Luo; D.      Wang; C.      Li

Abstract

Protein serine/threonine phosphatases are important cellular signaling molecules and play major roles in regulating many different functions including cell proliferation, senescence, programmed cell death, and oncogenic cell transformation. Among different serine/threonine phosphatases, PP-1 and PP-2A contribute to more than 90% phosphatase activities in eukaryotes. While the functions of PP-2A in cell transformation and tumorigenesis have been well established, the role of PP-1 in carcinogenesis remains to be further explored. Moreover, PP-1 exists in different isoforms, whether these isoforms have differential functions in tumorigenesis remains to be examined. In the present study, we demonstrated that in lung cancer 1299 cells, PP1α and PP- 1γ exist in an antagonizing balance. In the parent H1299 cells, PP-1γ is dominant, about 4-fold higher than that of PP-1α. Overexpression of PP-1α significantly down-regulates PP-1γ at both mRNA and protein levels. In contrast, knockdown of PP-1α leads to upregulation of PP-1γ. Moreover, overexpression of PP-1α significantly attenuates the ability of the H1299 cells in promoting tumorigenicity as tested in immuno-deficient nude mice. This attenuation is derived from the halted cell cycle progression, which is largely attributed by the changed RB-E2F activity. Together, our results demonstrate that PP-1α and PP-1γ not only antagonize each other in lung cancer cells, but also display differential functions in tumorigenicity.

Keywords: Cell proliferation, cyclin, dephosphorylation, E2F, lung cancer, PP-1α, PP-1γ, protein serine/threonine phosphatase-1, RB, tumorigenesis