title: The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer.
abstract: The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Read
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Seed
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Bhavika
authors.initials: B
authors.lastname: Modasia
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Perkin P K
authors.initials: PP
authors.lastname: Kwan
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Sharma
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Vicki E
authors.initials: VE
authors.lastname: Smith
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Watkins
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Sukhchain
authors.initials: S
authors.lastname: Bansal
authors.affiliation: University of Ferrara, Ferrara, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gagliano
authors.affiliation: Department of Pediatrics, University of British Columbia, Canada.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Stratford
authors.affiliation: School of Cancer Sciences, University of Birmingham, UK.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ismail
authors.affiliation: The Babraham Institute, Babraham Research Campus, UK.
authors.forename: Michael J O
authors.initials: MJ
authors.lastname: Wakelam
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Dae S
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Centre for Liver Research and NIHR Centre for Biomedical Research Unit, University of Birmingham, UK.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ward
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Kristien
authors.initials: K
authors.lastname: Boelaert
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Franklyn
authors.affiliation: School of Cancer Sciences, University of Birmingham, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Turnell
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D008565:Membrane Proteins; C112633:PTTG1IP protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53
keywords: PTTG1IP; TP53; colon; colorectal tumorigenesis; oncogene