Characterization of mutant p53-based oncogenic mechanism: regulation of CPSF6

BORINI CARLA; IBARRA SOLANGE; GIRARDINI J.E.

Congreso; Molecular mechanisms in cell signaling and gene expresión. Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2013

P53 point mutants, besides losing the tumor suppressor function of the wt protein, may acquire novel activities that promote the development of aggressive and metastatic tumors. We have previously found that the prolil-isomerase Pin1 cooperates with mutant p53 to alter gene expression in breast cancer cells. In particular, both proteins induce the expression of 10 genes (Pin1/mutant p53 signature) whose expression is associated with the development of aggressive breast tumors. Among them we found CPSF6, which codes for a 68 kDa protein, belonging to the CFIm processing factor that regulates mRNA polyadenilation. Even if several aspects CFIm function in polyadenilation were described, little is known regarding how CPSF6 may be involved in human cancer. In order to understand the mechanisms underlying the pro-oncogenic role of CPSF6, we studied the consequences of overexpressing zebrafish Cpsf6 (DrCpsf6) during embryogenesis. We cloned the sequence of DrCpsf6 and we confirmed that it localizes in paraspeckles upon ectopic expression in cell lines. Surprisingly, we found that upon microinjection in zebrafish embryos, Cpsf6 expression is readily detectable at early stages but becomes almost completely absent at later stages, suggesting the existence of robust posttranslational regulatory mechanisms. Further studies showed that oncogenic signals do not alter subcellular localization.