The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer

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The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer. / Read, Martin L.; Seed, Robert I.; Modasia, Bhavika; Kwan, Perkin P.k.; Sharma, Neil; Smith, Vicki E.; Watkins, Rachel; Bansal, Sukhchain; Gagliano, Teresa; Stratford, Anna L.; Ismail, Tariq; Wakelam, Michael J.o.; Kim, Dae S.; Ward, Stephen T.; Boelaert, Kristien; Franklyn, Jayne A.; Turnell, Andrew S.; Mccabe, Christopher J.

In: Molecular Carcinogenesis, Vol. 55, No. 1, 01.2016, p. 15-26.

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Read, Martin L. ; Seed, Robert I. ; Modasia, Bhavika ; Kwan, Perkin P.k. ; Sharma, Neil ; Smith, Vicki E. ; Watkins, Rachel ; Bansal, Sukhchain ; Gagliano, Teresa ; Stratford, Anna L. ; Ismail, Tariq ; Wakelam, Michael J.o. ; Kim, Dae S. ; Ward, Stephen T. ; Boelaert, Kristien ; Franklyn, Jayne A. ; Turnell, Andrew S. ; Mccabe, Christopher J. / The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer. In: Molecular Carcinogenesis. 2016 ; Vol. 55, No. 1. pp. 15-26.

Bibtex

@article{27c90c3174e747459e2bfbdd5c22579f,
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.",
keywords = "colon, PTTG1IP, TP53, colorectal tumorigenesis, oncogene",
author = "Read, {Martin L.} and Seed, {Robert I.} and Bhavika Modasia and Kwan, {Perkin P.k.} and Neil Sharma and Smith, {Vicki E.} and Rachel Watkins and Sukhchain Bansal and Teresa Gagliano and Stratford, {Anna L.} and Tariq Ismail and Wakelam, {Michael J.o.} and Kim, {Dae S.} and Ward, {Stephen T.} and Kristien Boelaert and Franklyn, {Jayne A.} and Turnell, {Andrew S.} and Mccabe, {Christopher J.}",
year = "2016",
month = jan,
doi = "10.1002/mc.22254",
language = "English",
volume = "55",
pages = "15--26",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley",
number = "1",

}

RIS

TY - JOUR

T1 - The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer

AU - Read, Martin L.

AU - Seed, Robert I.

AU - Modasia, Bhavika

AU - Kwan, Perkin P.k.

AU - Sharma, Neil

AU - Smith, Vicki E.

AU - Watkins, Rachel

AU - Bansal, Sukhchain

AU - Gagliano, Teresa

AU - Stratford, Anna L.

AU - Ismail, Tariq

AU - Wakelam, Michael J.o.

AU - Kim, Dae S.

AU - Ward, Stephen T.

AU - Boelaert, Kristien

AU - Franklyn, Jayne A.

AU - Turnell, Andrew S.

AU - Mccabe, Christopher J.

PY - 2016/1

Y1 - 2016/1

N2 - 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.

AB - 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.

KW - colon

KW - PTTG1IP

KW - TP53

KW - colorectal tumorigenesis

KW - oncogene

U2 - 10.1002/mc.22254

DO - 10.1002/mc.22254

M3 - Article

C2 - 25408419

VL - 55

SP - 15

EP - 26

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

IS - 1

ER -