The University of Southampton
University of Southampton Institutional Repository

Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance

Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance
Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance
Background information. CtBP proteins have roles in the nucleus as transcriptional co-repressors, and in the cytoplasm in the maintenance of vesicular membranes. CtBPs are expressed from two genes, CTBP1 and CTBP2, mRNA products of which are alternatively spliced at their 5' ends to generate distinct protein isoforms. Extensive molecular and cellular analyses have identified CtBPs as regulators of pathways critical for tumour initiation, progression, and response to therapy. However little is known of the expression or regulation of CtBP isoforms in human cancer, nor the relative contribution of CTBP1 and CTBP2 to the tumour cell phenotype. Results. Expression of CtBP proteins, and CTBP1 and CTBP2 mRNA splice forms in breast cancer cell lines and tumour tissue were examined. CtBP1 proteins are identifiable as a single band on western blots and are ubiquitously detectable in breast tumour samples, by both western blotting and immunohistochemistry. CtBP1 is present in 6 of 6 breast cancer cell lines, though is barely detectable in SKBr3 cells due to reduced CTBP1 mRNA expression. In the cell lines, the predominant CTBP1 mRNA splice form encodes CtBP1-S protein; in tumours both major CTBP1 mRNA splice forms are variably expressed. CtBP2 proteins are ubiquitously expressed in all lines and tumour samples. The predominant CTBP2 mRNA encodes CtBP2-L, though an alternatively spliced form that encodes CtBP2-S, previously unidentified in humans, is expressed at low abundance. Both CtBP2-L and CtBP2-S are readily detectable as two distinct bands on western blots; here we show that the CTBP2-L mRNA is translated from two AUG codons to generate both CtBP2-L and CtBP2-S. We have also identified an auto-regulatory feedback mechanism whereby CtBP protein abundance is maintained in proliferating breast cancer cells through the post-transcriptional regulation of CtBP2. This feedback is disrupted by ultraviolet-C (UV-C) radiation, or exposure to cisplatin. Finally we demonstrate that CtBP1 and CtBP2 both have p53-dependent and -independent roles in suppressing the sensitivity of breast cancer cells to mechanistically diverse cancer chemotherapeutic agents. Conclusions. These studies support recent evidence that CtBP family proteins represent potential targets for therapeutic strategies for the treatment of cancer in general, and breast cancer in particular.
0248-4900
1-19
Birts, Charles N.
8689ddad-ba47-4ca6-82c5-001315dbd250
Harding, Rachael
bfde35b4-402c-4c36-bf39-5bc342ee970a
Soosaipillai, Gehan Bernard
8e4bb951-d0de-4305-9a2d-d924319eb304
Halder, Trisha
c0b93290-9920-426a-8666-b794e1ec6e2c
Azim-Araghi, Ali
6338a14d-f770-4945-8432-4c246b31f6f5
Darley, Matthew
7be23780-a781-4dd4-a74c-f5affbb79521
Cutress, Ramsey I
68ae4f86-e8cf-411f-a335-cdba51797406
Bateman, Adrian C.
28ae82e3-b93a-429a-81f5-04e8f1ff4cc7
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Birts, Charles N.
8689ddad-ba47-4ca6-82c5-001315dbd250
Harding, Rachael
bfde35b4-402c-4c36-bf39-5bc342ee970a
Soosaipillai, Gehan Bernard
8e4bb951-d0de-4305-9a2d-d924319eb304
Halder, Trisha
c0b93290-9920-426a-8666-b794e1ec6e2c
Azim-Araghi, Ali
6338a14d-f770-4945-8432-4c246b31f6f5
Darley, Matthew
7be23780-a781-4dd4-a74c-f5affbb79521
Cutress, Ramsey I
68ae4f86-e8cf-411f-a335-cdba51797406
Bateman, Adrian C.
28ae82e3-b93a-429a-81f5-04e8f1ff4cc7
Blaydes, Jeremy P.
e957f999-fd91-4f77-ad62-5b4ef069b15b

Birts, Charles N., Harding, Rachael, Soosaipillai, Gehan Bernard, Halder, Trisha, Azim-Araghi, Ali, Darley, Matthew, Cutress, Ramsey I, Bateman, Adrian C. and Blaydes, Jeremy P. (2010) Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance. Biology of the Cell, 103, 1-19. (doi:10.1042/BC20100067). (PMID:20964627)

Record type: Article

Abstract

Background information. CtBP proteins have roles in the nucleus as transcriptional co-repressors, and in the cytoplasm in the maintenance of vesicular membranes. CtBPs are expressed from two genes, CTBP1 and CTBP2, mRNA products of which are alternatively spliced at their 5' ends to generate distinct protein isoforms. Extensive molecular and cellular analyses have identified CtBPs as regulators of pathways critical for tumour initiation, progression, and response to therapy. However little is known of the expression or regulation of CtBP isoforms in human cancer, nor the relative contribution of CTBP1 and CTBP2 to the tumour cell phenotype. Results. Expression of CtBP proteins, and CTBP1 and CTBP2 mRNA splice forms in breast cancer cell lines and tumour tissue were examined. CtBP1 proteins are identifiable as a single band on western blots and are ubiquitously detectable in breast tumour samples, by both western blotting and immunohistochemistry. CtBP1 is present in 6 of 6 breast cancer cell lines, though is barely detectable in SKBr3 cells due to reduced CTBP1 mRNA expression. In the cell lines, the predominant CTBP1 mRNA splice form encodes CtBP1-S protein; in tumours both major CTBP1 mRNA splice forms are variably expressed. CtBP2 proteins are ubiquitously expressed in all lines and tumour samples. The predominant CTBP2 mRNA encodes CtBP2-L, though an alternatively spliced form that encodes CtBP2-S, previously unidentified in humans, is expressed at low abundance. Both CtBP2-L and CtBP2-S are readily detectable as two distinct bands on western blots; here we show that the CTBP2-L mRNA is translated from two AUG codons to generate both CtBP2-L and CtBP2-S. We have also identified an auto-regulatory feedback mechanism whereby CtBP protein abundance is maintained in proliferating breast cancer cells through the post-transcriptional regulation of CtBP2. This feedback is disrupted by ultraviolet-C (UV-C) radiation, or exposure to cisplatin. Finally we demonstrate that CtBP1 and CtBP2 both have p53-dependent and -independent roles in suppressing the sensitivity of breast cancer cells to mechanistically diverse cancer chemotherapeutic agents. Conclusions. These studies support recent evidence that CtBP family proteins represent potential targets for therapeutic strategies for the treatment of cancer in general, and breast cancer in particular.

Full text not available from this repository.

More information

Published date: 25 November 2010

Identifiers

Local EPrints ID: 166261
URI: https://eprints.soton.ac.uk/id/eprint/166261
ISSN: 0248-4900
PURE UUID: 0797940b-815d-490f-8454-fbe3cfb9ddfe
ORCID for Charles N. Birts: ORCID iD orcid.org/0000-0002-0368-8766
ORCID for Jeremy P. Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

Catalogue record

Date deposited: 26 Oct 2010 12:18
Last modified: 18 Jul 2019 01:03

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×