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The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells

Cdr2 is a tumor antigen expressed in a high percentage of breast and ovarian tumors and is the target of a naturally occurring tumor immune response in patients with paraneoplastic cerebellar degeneration, but little is known of its regulation or function in cancer cells. Here we find that cdr2 is c...

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Autores principales: O'Donovan, Kevin J., Diedler, Jennifer, Couture, Graeme C., Fak, John J., Darnell, Robert B.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850929/
https://www.ncbi.nlm.nih.gov/pubmed/20383333
http://dx.doi.org/10.1371/journal.pone.0010045
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author O'Donovan, Kevin J.
Diedler, Jennifer
Couture, Graeme C.
Fak, John J.
Darnell, Robert B.
author_facet O'Donovan, Kevin J.
Diedler, Jennifer
Couture, Graeme C.
Fak, John J.
Darnell, Robert B.
author_sort O'Donovan, Kevin J.
collection PubMed
description Cdr2 is a tumor antigen expressed in a high percentage of breast and ovarian tumors and is the target of a naturally occurring tumor immune response in patients with paraneoplastic cerebellar degeneration, but little is known of its regulation or function in cancer cells. Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. Loss of cdr2 leads to functional consequences for dividing cells, as they show aberrant mitotic spindle formation and impaired proliferation. Conversely, cdr2 overexpression is able to drive cell proliferation in tumors. Together, these data indicate that the onconeural antigen cdr2 acts during mitosis in cycling cells, at least in part through interactions with c-myc, to regulate a cascade of actions that may present new targeting opportunities in gynecologic cancer.
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spelling pubmed-28509292010-04-09 The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells O'Donovan, Kevin J. Diedler, Jennifer Couture, Graeme C. Fak, John J. Darnell, Robert B. PLoS One Research Article Cdr2 is a tumor antigen expressed in a high percentage of breast and ovarian tumors and is the target of a naturally occurring tumor immune response in patients with paraneoplastic cerebellar degeneration, but little is known of its regulation or function in cancer cells. Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. Loss of cdr2 leads to functional consequences for dividing cells, as they show aberrant mitotic spindle formation and impaired proliferation. Conversely, cdr2 overexpression is able to drive cell proliferation in tumors. Together, these data indicate that the onconeural antigen cdr2 acts during mitosis in cycling cells, at least in part through interactions with c-myc, to regulate a cascade of actions that may present new targeting opportunities in gynecologic cancer. Public Library of Science 2010-04-07 /pmc/articles/PMC2850929/ /pubmed/20383333 http://dx.doi.org/10.1371/journal.pone.0010045 Text en O'Donovan et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
O'Donovan, Kevin J.
Diedler, Jennifer
Couture, Graeme C.
Fak, John J.
Darnell, Robert B.
The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells
title The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells
title_full The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells
title_fullStr The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells
title_full_unstemmed The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells
title_short The Onconeural Antigen cdr2 Is a Novel APC/C Target that Acts in Mitosis to Regulate C-Myc Target Genes in Mammalian Tumor Cells
title_sort onconeural antigen cdr2 is a novel apc/c target that acts in mitosis to regulate c-myc target genes in mammalian tumor cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850929/
https://www.ncbi.nlm.nih.gov/pubmed/20383333
http://dx.doi.org/10.1371/journal.pone.0010045
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