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764 results on '"VOUSDEN, KAREN H."'

101. Transcriptional activation by p53 correlates with suppression of growth but not transformation

Author

Crook, Tim, Marston, Nicola J., Sara, Elizabeth A., and Vousden, Karen H.

Subjects
Tumor suppressor genes -- Analysis, Genetic transcription -- Regulation, Genetic transformation -- Analysis, Biological sciences
Abstract

Experimental analysis of several naturally occurring and truncation tumor suppressor gene p53 mutants reveals a direct relation between p53-induced growth suppression and transcription activation. However, the mutants are capable of transactivation and transformation activities, indicating that p53 genes do not affect transformation. Cell lines containing the expression of endogenous p53 transactivating functional proteins have a high p53 transcriptional activity.

Published
1994

109. Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer

Author

Humpton, Timothy J., primary, Alagesan, Brinda, additional, DeNicola, Gina M., additional, Lu, Dan, additional, Yordanov, Georgi N., additional, Leonhardt, Carl S., additional, Yao, Melissa A., additional, Alagesan, Priya, additional, Zaatari, Maya N., additional, Park, Youngkyu, additional, Skepper, Jeremy N., additional, Macleod, Kay F., additional, Perez-Mancera, Pedro A., additional, Murphy, Michael P., additional, Evan, Gerard I., additional, Vousden, Karen H., additional, and Tuveson, David A., additional

Published
2019
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113. The ERBB network facilitates KRAS-driven lung tumorigenesis

Author

Kruspig, Björn, primary, Monteverde, Tiziana, additional, Neidler, Sarah, additional, Hock, Andreas, additional, Kerr, Emma, additional, Nixon, Colin, additional, Clark, William, additional, Hedley, Ann, additional, Laing, Sarah, additional, Coffelt, Seth B., additional, Le Quesne, John, additional, Dick, Craig, additional, Vousden, Karen H., additional, Martins, Carla P., additional, and Murphy, Daniel J., additional

Published
2018
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116. Cytoplasmic ASPP1 inhibits apoptosis through the control of YAP

Author

Vigneron, Arnaud M., Ludwig, Robert L., and Vousden, Karen H.

Subjects
Apoptosis -- Research, Enzyme inhibitors -- Research, Phosphorylation -- Analysis, Genetic transcription -- Research, Tumor suppressor genes -- Research, Biological sciences
Published
2010

117. CRISPR/Cas9-mediated Trp53 and Brca2 knockout to generate improved murine models of ovarian high grade serous carcinoma

Author

Walton, Josephine, Blagih, Julianna, Ennis, Darren, Leung, Elaine, Dowson, Suzanne, Farquharson, Malcolm, Tookman, Laura A., Orange, Clare, Athineos, Dimitris, Mason, Susan, Stevenson, David, Blyth, Karen, Strathdee, Douglas, Balkwill, Frances R., Vousden, Karen H., Lockley, Michelle, and McNeish, Iain A.

Abstract

There is a need for transplantable murine models of ovarian high grade serous carcinoma (HGSC) with regard to mutations in the human disease, to assist investigations of the relationships between tumor genotype, chemotherapy response and immune microenvironment. In addressing this need, we performed whole exome sequencing of ID8, the most widely-used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400x with 90% exons sequenced >50x. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, Rb1) and p53 remained transcriptionally active. Homologous recombination in ID8 remained intact in functional assays. Further, we found no mutations typical of clear cell carcinoma (Arid1A, Pik3ca), low grade serous carcinoma (Braf), endometrioid (Ctnnb1) or mucinous (Kras) carcinomas. Using CRISPR/Cas9 gene editing, we modeled HGSC by generating novel ID8 derivatives that harbored single (Trp53-/-) or double (Trp53-/-;Brca2-/-) suppressor gene deletions. In these mutants, loss of p53 alone was sufficient to increase the growth rate of orthotopic tumors with significant effects observed on the immune microenvironment. Specifically, p53 loss increased expression of the myeloid attractant CCL and promoted the infiltration of immunosuppressive myeloid cell populations into primary tumors and their ascites. In Trp53-/-;Brca2-/- mutant cells, we documented a relative increase in sensitivity to the PARP inhibitor rucaparib and slower orthotopic tumor growth compared to Trp53-/- cells, with an appearance of intra-tumoral tertiary lymphoid structures rich in CD3+ T cells. This work validates new CRISPR-generated models of HGSC to investigate its biology and promote mechanism-based therapeutics discovery.

Published
2016

118. Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice

Author

Humpton, Timothy J., Nomura, Koji, Weber, Julia, Magnussen, Helge M., Hock, Andreas K., Nixon, Colin, Dhayade, Sandeep, Stevenson, David, Huang, Danny T., Strathdee, Douglas, Blyth, Karen, and Vousden, Karen H.

Abstract

In this study, Humpton et al. present a mouse MDM2 mutant (MDM2 I438K) analogous to human cancer cell mutations that restrains p53 sufficiently for normal growth, but exhibits an enhanced stress response in vitro. Their results are a proof of principle model for therapeutic development, and promote an approach that would inhibit MDM2 E3 activity without preventing MDM2/p53 binding.

Published
2021
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119. Corrigendum: Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Author

Maddocks, Oliver D. K., Athineos, Dimitris, Cheung, Eric C., Lee, Pearl, Zhang, Tong, van den Broek, Niels J. F., Mackay, Gillian M., Labuschagne, Christiaan F., Gay, David, Kruiswijk, Flore, Blagih, Julianna, Vincent, David F., Campbell, Kirsteen J., Ceteci, Fatih, Sansom, Owen J., Blyth, Karen, and Vousden, Karen H.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Oliver D. K. Maddocks; Dimitris Athineos; Eric C. Cheung; Pearl Lee; Tong Zhang; Niels J. F. van den Broek; Gillian M. Mackay; Christiaan F. Labuschagne; David Gay; Flore Kruiswijk; [...]

Published
2017
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120. TIGAR, a p53-inducible regulator of glycolysis and apoptosis

Author

Bensaad, Karim, Tsuruta, Atsushi, Selak, Mary A., Vidal, M. Nieves Calvo, Nakano, Katsunori, Bartrons, Ramon, Gottlieb, Eyal, and Vousden, Karen H.

Subjects
Apoptosis -- Research, Glycolysis -- Research, Tumor suppressor genes -- Research, Genetic research, Biological sciences
Abstract

A p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator) is identified that lowers fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. The expression of TIGAR modulates the apoptotic response to p53 and the decrease of intracellular ROS levels in response to TIGAR plays a role in the ability of p53 to protect from the accumulation of genomic damage.

Published
2006

121. P53 and prognosis: New insights and further complexity

Author

Vousden, Karen H. and Prives, Carol

Subjects
Oncogenes -- Research, Gene mutations -- Research, Cancer -- Care and treatment, Cancer -- Research, Biological sciences
Abstract

Researches provide evidence that levels of Mdm2 in humans or presence of mutant forms of p53 in mice could have profound impacts on survival and tumorigenesis. The findings are also expected to lead to new diagnosis and therapeutic approaches to treating cancer patients.

Published
2005

122. Erratum: Corrigendum: Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Author

Maddocks, Oliver D. K., primary, Athineos, Dimitris, additional, Cheung, Eric C., additional, Lee, Pearl, additional, Zhang, Tong, additional, van den Broek, Niels J. F., additional, Mackay, Gillian M., additional, Labuschagne, Christiaan F., additional, Gay, David, additional, Kruiswijk, Flore, additional, Blagih, Julianna, additional, Vincent, David F., additional, Campbell, Kirsteen J., additional, Ceteci, Fatih, additional, Sansom, Owen J., additional, Blyth, Karen, additional, and Vousden, Karen H., additional

Published
2017
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124. Development of an inducible mouse model of iRFP713 to track recombinase activity and tumour development in vivo

Author

Hock, Andreas K., primary, Cheung, Eric C., additional, Humpton, Timothy J., additional, Monteverde, Tiziana, additional, Paulus-Hock, Viola, additional, Lee, Pearl, additional, McGhee, Ewan, additional, Scopelliti, Alessandro, additional, Murphy, Daniel J., additional, Strathdee, Douglas, additional, Blyth, Karen, additional, and Vousden, Karen H., additional

Published
2017
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126. The secret life of histones

Author

Gillespie, David A.F. and Vousden, Karen H.

Subjects
Apoptosis -- Physiological aspects, DNA damage -- Physiological aspects, Histones -- Physiological aspects, Biological sciences
Published
2003

127. Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity

Author

Haller, Martina, Hock, Andreas K., Giampazolias, Evangelos, Oberst, Andrew, Green, Douglas R., Debnath, Jayanta, Ryan, Kevin M., Vousden, Karen H., and Tait, Stephen W. G.

Subjects
proteasomal degradation, UB, ubiquitin, Proteasome Endopeptidase Complex, Basic Research Papers, Act D, actinomycin D, ATG12, ubiquitin-like protein, Apoptosis, BCL2L1, BCL2-like 1, ubiquitination, Mice, CHX, cycloheximide, ATG, autophagy-related, BH3, BCL2 homology domain 3, Autophagy, Animals, Humans, Cell Death, LC3/MAP1LC3, microtubule-associated protein 1 light chain 3, MEF, mouse embryonic fibroblast, Mitochondria, RNAi, RNA interference, UBL, ubiquitin-like protein, HBSS, Hank's balanced salt solution, Ubiquitin-Conjugating Enzymes, Small Ubiquitin-Related Modifier Proteins, Microtubule-Associated Proteins, Protein Processing, Post-Translational, Autophagy-Related Protein 12
Abstract

During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12-ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12.

Published
2014

137. PHD 1 regulates p53‐mediated colorectal cancer chemoresistance

Author

Deschoemaeker, Sofie, primary, Di Conza, Giusy, additional, Lilla, Sergio, additional, Martín‐Pérez, Rosa, additional, Mennerich, Daniela, additional, Boon, Lise, additional, Hendrikx, Stefanie, additional, Maddocks, Oliver DK, additional, Marx, Christian, additional, Radhakrishnan, Praveen, additional, Prenen, Hans, additional, Schneider, Martin, additional, Myllyharju, Johanna, additional, Kietzmann, Thomas, additional, Vousden, Karen H, additional, Zanivan, Sara, additional, and Mazzone, Massimiliano, additional

Published
2015
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144. Savior and slayer: the two faces of p53

Author

Bensaad, Karim and Vousden, Karen H

Abstract

Author(s): Karim Bensaad [1]; Karen H Vousden [1] The tumor suppressor protein p53 prevents the development of cancer by inhibiting the proliferation of nascent cancer cells, which depends in part [...]

Published
2005
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145. Modulating the therapeutic response of tumours to dietary serine and glycine starvation.

Author

Maddocks, Oliver D. K., Athineos, Dimitris, Cheung, Eric C., Lee, Pearl, Zhang, Tong, van den Broek, Niels J. F., Mackay, Gillian M., Labuschagne, Christiaan F., Gay, David, Kruiswijk, Flore, Blagih, Julianna, Vincent, David F., Campbell, Kirsteen J., Ceteci, Fatih, Sansom, Owen J., Blyth, Karen, and Vousden, Karen H.

Abstract

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis. [ABSTRACT FROM AUTHOR]

Published
2017
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