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p53 is activated in response to disruption of the pre-mRNA splicing machinery

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p53 is activated in response to disruption of the pre-mRNA splicing machinery. / Allende-Vega, N.; Dayal, S.; Agarwala, U.; Sparks, A.; Bourdon, J.-C.; Saville, M. K. (Lead / Corresponding author).

In: Oncogene, Vol. 32, No. 1, 03.01.2013, p. 1-14.

Research output: Contribution to journalArticle

Harvard

Allende-Vega, N, Dayal, S, Agarwala, U, Sparks, A, Bourdon, J-C & Saville, MK 2013, 'p53 is activated in response to disruption of the pre-mRNA splicing machinery' Oncogene, vol 32, no. 1, pp. 1-14., 10.1038/onc.2012.38

APA

Allende-Vega, N., Dayal, S., Agarwala, U., Sparks, A., Bourdon, J-C., & Saville, M. K. (2013). p53 is activated in response to disruption of the pre-mRNA splicing machinery. Oncogene, 32(1), 1-14. 10.1038/onc.2012.38

Vancouver

Allende-Vega N, Dayal S, Agarwala U, Sparks A, Bourdon J-C, Saville MK. p53 is activated in response to disruption of the pre-mRNA splicing machinery. Oncogene. 2013 Jan 3;32(1):1-14. Available from: 10.1038/onc.2012.38

Author

Allende-Vega, N.; Dayal, S.; Agarwala, U.; Sparks, A.; Bourdon, J.-C.; Saville, M. K. (Lead / Corresponding author) / p53 is activated in response to disruption of the pre-mRNA splicing machinery.

In: Oncogene, Vol. 32, No. 1, 03.01.2013, p. 1-14.

Research output: Contribution to journalArticle

Bibtex - Download

@article{27820d21c12b4cfd8f74f3285c14e438,
title = "p53 is activated in response to disruption of the pre-mRNA splicing machinery",
keywords = "PROTEIN, Mdm2, DNA-DAMAGE, GENOTOXIC STRESS, IN-VIVO, FACTOR SF3B, spliceosome, splicing, p53, DEUBIQUITINATING ENZYME USP2A, EMERGING ROLE, TRANSCRIPTION, TG003, MDM2, MdmX, CANCER-CELLS",
author = "N. Allende-Vega and S. Dayal and U. Agarwala and A. Sparks and J.-C. Bourdon and Saville, {M. K.}",
note = "MEDLINE® is the source for the MeSH terms of this document.",
year = "2013",
doi = "10.1038/onc.2012.38",
volume = "32",
number = "1",
pages = "1--14",
journal = "Oncogene",
issn = "0950-9232",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - p53 is activated in response to disruption of the pre-mRNA splicing machinery

A1 - Allende-Vega,N.

A1 - Dayal,S.

A1 - Agarwala,U.

A1 - Sparks,A.

A1 - Bourdon,J.-C.

A1 - Saville,M. K.

AU - Allende-Vega,N.

AU - Dayal,S.

AU - Agarwala,U.

AU - Sparks,A.

AU - Bourdon,J.-C.

AU - Saville,M. K.

PY - 2013/1/3

Y1 - 2013/1/3

N2 - In this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G 1 cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach. © 2013 Macmillan Publishers Limited.

AB - In this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G 1 cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach. © 2013 Macmillan Publishers Limited.

KW - PROTEIN

KW - Mdm2

KW - DNA-DAMAGE

KW - GENOTOXIC STRESS

KW - IN-VIVO

KW - FACTOR SF3B

KW - spliceosome

KW - splicing

KW - p53

KW - DEUBIQUITINATING ENZYME USP2A

KW - EMERGING ROLE

KW - TRANSCRIPTION

KW - TG003

KW - MDM2

KW - MdmX

KW - CANCER-CELLS

UR - http://www.scopus.com/inward/record.url?scp=84871985001&partnerID=8YFLogxK

U2 - 10.1038/onc.2012.38

DO - 10.1038/onc.2012.38

M1 - Article

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 1

VL - 32

SP - 1

EP - 14

ER -

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