Research Papers:

Functional consequence of the p53 codon 72 polymorphism in colorectal cancer

Venkat R. Katkoori, Upender Manne, Lakshmi S. Chaturvedi, Marc D. Basson, Pam Haan, Daniel Coffey and Harvey L. Bumpers _

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Oncotarget. 2017; 8:76574-76586. https://doi.org/10.18632/oncotarget.20580

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Venkat R. Katkoori1, Upender Manne2, Lakshmi S. Chaturvedi3, Marc D. Basson3, Pam Haan1, Daniel Coffey4 and Harvey L. Bumpers1

1Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA

2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

3Department of Surgery, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND, USA

4Capital Colorectal Surgery, Lansing, MI, USA

Correspondence to:

Harvey L. Bumpers, email: [email protected]

Keywords: p53, codon 72 polymorphism, p38MAPK, EMT, CREB

Received: May 23, 2017     Accepted: August 16, 2017     Published: August 29, 2017


Background: The codon 72 polymorphism in p53 has been implicated in colorectal cancer (CRC) risk, prognosis and CRC health disparities. We examined the functional consequence of this polymorphism in CRC.

Experimental Design: Plasmids (pCMV6) that express different phenotypes of p53 [p53 wild type (wt) at codon 72 (R72wt), R72wt with mutation at codon 273 cysteine (R72273Cys), p53 mutation at codon 72 (P72wt) and P72wt with mutation at codon 273 (P72273Cys)] were constructed. The CRC cell line Caco2, which does not express p53 for in vitro studies, was used as host. CRC xenografts were established in severe combined immunodeficient (SCID) mice using established cell lines. CRC surgical specimens, corresponding normal colon, and tumor xenografts were sequenced for codon 72 polymorphism of p53. Proteins signaling mechanisms were evaluated to assess the functional consequence of P72 phenotype of p53.

Results: This study demonstrated a significantly increased survival of cells expressing P72wt, mutant phenotype, versus R72wt phenotype. WB analyses revealed that P72wt induced activation of p38 and RAF/MEK/ extracellular signal-regulated kinase (ERK) MAP kinases. Activation of CREB was found to be higher in tumors that exhibit P72 phenotype. Metastatic lesions of CRC expressed more phospho-CREB than non-metastatic lesions. The expression of P72wt promoted CRC metastasis.

Conclusions: P72 contributes to the aggressiveness of CRC. Because P72 is over-expressed in CRC, specifically in African-American patients, this suggests a role for P72 in cancer health disparities. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251 & U54CA118948.

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