title: The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells.
abstract: The PTTG1-binding factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a protooncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity-ligation assays, we show that PBF binds specifically to p53 in thyroid cells and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroid-specific PBF overexpression (transgenic PBF mice), which had significantly increased genetic instability as indicated by fluorescent inter simple sequence repeat-PCR analysis. Consistent with this, approximately 40% of all DNA repair genes examined were repressed in transgenic PBF primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51, and Xrcc3. Our data also revealed that PBF induction resulted in up-regulation of the E2 enzyme Rad6 in murine thyrocytes and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the protooncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, in which PBF is generally overexpressed and p53 mutations are rare compared with other tumor types.
authors: School of Clinical and Experimental Medicine (M.L.R., R.I.S., J.C.W.F., B.M., G.A.R., R.J.W., V.E.S., P.K.K., N.S., O.M.D., K.B., J.A.F., C.J.M.) and School of Cancer Sciences (A.S.T.), University of Birmingham, Birmingham, United Kingdom; Department of Medical Sciences (T.G.), University of Ferrara, Ferrara, Italy; Department of Pediatrics (A.L.S.), University of British Columbia, Vancouver, British Columbia, Canada; and University Hospitals Birmingham National Health Service Foundation Trust (J.C.W.), Birmingham, United Kingdom.
authors: Martin L
authors: ML
authors: Read
authors: Robert I
authors: RI
authors: Seed
authors: Jim C W
authors: JC
authors: Fong
authors: Bhavika
authors: B
authors: Modasia
authors: Gavin A
authors: GA
authors: Ryan
authors: Rachel J
authors: RJ
authors: Watkins
authors: Teresa
authors: T
authors: Gagliano
authors: Vicki E
authors: VE
authors: Smith
authors: Anna L
authors: AL
authors: Stratford
authors: Perkin K
authors: PK
authors: Kwan
authors: Neil
authors: N
authors: Sharma
authors: Olivia M
authors: OM
authors: Dixon
authors: John C
authors: JC
authors: Watkinson
authors: Kristien
authors: K
authors: Boelaert
authors: Jayne A
authors: JA
authors: Franklyn
authors: Andrew S
authors: AS
authors: Turnell
authors: Christopher J
authors: CJ
authors: McCabe
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D004260:DNA Repair; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D013961:Thyroid Gland / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C112633:PTTG1IP protein, human; C550910:PTTG1IP protein, mouse; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin