title: Pax8 has a critical role in epithelial cell survival and proliferation.
abstract: The transcription factor Pax8, a member of the Paired-box gene family, is a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well characterized with respect to its role in regulating genes responsible for thyroid differentiation, its involvement in cell survival and proliferation has been hypothesized but remains unclear. Here, we show that Pax8 overexpression significantly increases proliferation and colony-forming efficiency of Fischer rat thyroid line 5 epithelial cells, although it is not sufficient to overcome their hormone dependence. More interestingly, we show that Pax8-specific silencing induces apoptosis through a p53-dependent pathway that involves caspase-3 activation and cleavage of poly(ADP)ribose polymerase. Our data indicate that tumor protein 53 induced nuclear protein 1 (tp53inp1), a positive regulator of p53-dependent cell cycle arrest and apoptosis, is a transcriptional target of Pax8 and is upregulated by Pax8 knockdown. Remarkably, tp53inp1 silencing significantly abolishes Pax8-induced apoptosis thus suggesting that tp53inp1 may be the mediator of the observed effects. In conclusion, our data highlight that Pax8 is required for the survival of differentiated epithelial cells and its expression levels are able to modulate the proliferation rate of such cells.
authors.affiliation: CNR-National Research Council, Institute of Experimental Endocrinology and Oncology (IEOS), Naples, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Di Palma
authors.forename: M G
authors.initials: MG
authors.lastname: Filippone
authors.forename: G M
authors.initials: GM
authors.lastname: Pierantoni
authors.forename: A
authors.initials: A
authors.lastname: Fusco
authors.forename: S
authors.initials: S
authors.lastname: Soddu
authors.forename: M
authors.initials: M
authors.lastname: Zannini
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D004847:Epithelial Cells / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000502:physiology*; D034622:RNA Interference; D051381:Rats
chemical_list: D051017:Apoptosis Regulatory Proteins; D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; C498966:Tp53INP1 protein, rat