1. The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer
- Author
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Martin L, Read, Robert I, Seed, Bhavika, Modasia, Perkin P K, Kwan, Neil, Sharma, Vicki E, Smith, Rachel J, Watkins, Sukhchain, Bansal, Teresa, Gagliano, Anna L, Stratford, Tariq, Ismail, Michael J O, Wakelam, Dae S, Kim, Stephen T, Ward, Kristien, Boelaert, Jayne A, Franklyn, Andrew S, Turnell, and Christopher J, McCabe
- Subjects
p53 ,Intracellular Signaling Peptides and Proteins ,Ubiquitination ,Gene Expression ,Membrane Proteins ,Ambientale ,Prognosis ,Proto-Oncogene Mas ,Genomic Instability ,PBF ,Gene Expression Regulation, Neoplastic ,Mice ,Cell Line, Tumor ,Animals ,Humans ,Neoplasm Invasiveness ,Protein Interaction Domains and Motifs ,RNA, Messenger ,Tumor Suppressor Protein p53 ,Colorectal Neoplasms ,Tumor Stem Cell Assay ,Protein Binding - 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 (P0.0001) 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%; P0.01) 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 (P0.05), 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.
- Published
- 2016