Beatson Institute for Cancer Research

Glasgow, United Kingdom

Beatson Institute for Cancer Research

Glasgow, United Kingdom
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Rath O.,Beatson Institute for Cancer Research | Kozielski F.,Beatson Institute for Cancer Research
Nature Reviews Cancer | Year: 2012

Kinesins are a family of molecular motors that travel unidirectionally along microtubule tracks to fulfil their many roles in intracellular transport or cell division. Over the past few years kinesins that are involved in mitosis have emerged as potential targets for cancer drug development. Several compounds that inhibit two mitotic kinesins (EG5 (also known as KIF11) and centromere-associated protein E (CENPE)) have entered Phase I and II clinical trials either as monotherapies or in combination with other drugs. Additional mitotic kinesins are currently being validated as drug targets, raising the possibility that the range of kinesin-based drug targets may expand in the future. © 2012 Macmillan Publishers Limited. All rights reserved.


Rath N.,Beatson Institute for Cancer Research | Olson M.F.,Beatson Institute for Cancer Research
EMBO Reports | Year: 2012

The Rho-associated (ROCK) serine/threonine kinases have emerged as central regulators of the actomyosin cytoskeleton, their main purpose being to promote contractile force generation. Aided by the discovery of effective inhibitors such as Y27632, their roles in cancer have been extensively explored with particular attention focused on motility, invasion and metastasis. Recent studies have revealed a surprisingly diverse range of functions of ROCK. These insights could change the way ROCK inhibitors might be used in cancer therapy to include the targeting of stromal rather than tumour cells, the concomitant blocking of ROCK and proteasome activity in K-Ras-driven lung cancers and the combination of ROCK with tyrosine kinase inhibitors for treating haematological malignancies such as chronic myeloid leukaemia. Despite initial optimism for therapeutic efficacy of ROCK inhibition for cancer treatment, no compounds have progressed into standard therapy so far. However, by carefully defining the key cancer types and expanding the appreciation of ROCK's role in cancer beyond being a cell-autonomous promoter of tumour cell invasion and metastasis, the early promise of ROCK inhibitors for cancer therapy might still be realized. © 2012 EUROPEAN MOLECULAR BIOLOGY ORGANIZATION.


King J.S.,Beatson Institute for Cancer Research
Trends in Molecular Medicine | Year: 2012

Changes in the mechanical environment are a universal challenge for cells, and mechanical cues regulate tissue structure and cell physiology throughout life. Autophagy is an important degradative pathway, fulfilling a wide range of roles in survival, homeostasis and adaptation. The two are connected, and in vitro, autophagy is rapidly induced in cells exposed to mechanical compression. In vivo, autophagy is also induced in several medically relevant circumstances that are also under mechanical stress such as bone and muscle homeostasis and tissue injury. The induction of autophagy has wide-ranging effects on cells. In this article, I propose that the autophagic response to mechanical stress is an important factor in a wide range of both physiological and pathological settings. © 2012 Elsevier Ltd.


Mah L.Y.,Beatson Institute for Cancer Research | Ryan K.M.,Beatson Institute for Cancer Research
Cold Spring Harbor Perspectives in Biology | Year: 2012

(Macro)autophagy is a cellular membrane trafficking process that serves to deliver cytoplasmic constituents to lysosomes for degradation. At basal levels, it is critical for maintaining cytoplasmic as well as genomic integrity and is therefore key to maintaining cellular homeostasis. Autophagy is also highly adaptable and can be modified to digest specific cargoes to bring about selective effects in response to numerous forms of intracellular and extracellular stress. It is not a surprise, therefore, that autophagy has a fundamental role in cancer and that perturbations in autophagy can contribute to malignant disease. We review here the roles of autophagy in various aspects of tumor suppression including the response of cells to nutrient and hypoxic stress, the control of programmed cell death, and the connection to tumor-associated immune responses. © 2011 Cold Spring Harbor Laboratory Press.


Long J.S.,Beatson Institute for Cancer Research | Ryan K.M.,Beatson Institute for Cancer Research
Oncogene | Year: 2012

Cancer is a multifaceted disease comprising a combination of genetic, metabolic and signalling aberrations, which severely disrupt the normal homeostasis of cell growth and death. Many oncogenic events while promoting tumour development also increase the sensitivity of cells to cell death stimuli including chemotherapeutic drugs. As a result, tumour cells often acquire the ability to evade death by inactivating cell death pathways that normally function to eliminate damaged and harmful cells. The impairment of cell death function is also often the reason for the development of chemotherapeutic resistance encountered during treatment. It is therefore necessary to achieve a comprehensive understanding of existing cell death pathways and the relevant regulatory components involved, with the intention of identifying new strategies to kill cancer cells. This review provides an insightful overview of the common forms of cell death signalling pathways, the interactions between these pathways and the ways in which these pathways are deregulated in cancer. We also discuss the emerging therapies targeted at activating or restoring cell death pathways to induce tumour cell death, which are currently being tested in clinical trials. © 2012 Macmillan Publishers Limited All rights reserved.


Liu E.Y.,Beatson Institute for Cancer Research | Ryan K.M.,Beatson Institute for Cancer Research
Journal of Cell Science | Year: 2012

Autophagy is an evolutionarily conserved catabolic pathway that has multiple roles in carcinogenesis and cancer therapy. It can inhibit the initiation of tumorigenesis through limiting cytoplasmic damage, genomic instability and inflammation, and the loss of certain autophagy genes can lead to cancer. Conversely, autophagy can also assist cells in dealing with stressful metabolic environments, thereby promoting cancer cell survival. In fact, some cancers rely on autophagy to survive and progress. Furthermore, tumour cells can exploit autophagy to cope with the cytotoxicity of certain anticancer drugs. By contrast, it appears that certain therapeutics require autophagy for the effective killing of cancer cells. Despite these dichotomies, it is clear that autophagy has an important, if complex, role in cancer. This is further exemplified by the fact that autophagy is connected with major cancer networks, including those driven by p53, mammalian target of rapamycin (mTOR), RAS and glutamine metabolism. In this Commentary, we highlight recent advances in our understanding of the role that autophagy has in cancer and discuss current strategies for targeting autophagy for therapeutic gain. © 2012. Published by The Company of Biologists Ltd.


Muller P.A.J.,Beatson Institute for Cancer Research | Vousden K.H.,Beatson Institute for Cancer Research
Nature Cell Biology | Year: 2013

In the past fifteen years, it has become apparent that tumour-associated p53 mutations can provoke activities that are different to those resulting from simply loss of wild-type tumour-suppressing p53 function. Many of these mutant p53 proteins acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival. Here we highlight some of the emerging molecular mechanisms through which mutant p53 proteins can exert these oncogenic functions. © 2013 Macmillan Publishers Limited. All rights reserved.


Hock A.K.,Beatson Institute for Cancer Research | Vousden K.H.,Beatson Institute for Cancer Research
Cell | Year: 2012

p53 is a key tumor suppressor protein that has numerous functions. Its primary mode of action has generally been ascribed to the induction of cell-cycle arrest, apoptosis, or senescence upon stress. Li et al. challenge this dogma with evidence that all three of these programs are dispensable for p53's tumor suppressive role. © 2012 Elsevier Inc.


White R.J.,Beatson Institute for Cancer Research
Nature Reviews Genetics | Year: 2011

RNA polymerase (Pol) III is highly specialized for the production of short non-coding RNAs. Once considered to be under relatively simple controls, recent studies using chromatin immunoprecipitation followed by sequencing (ChIP-seq) have revealed unexpected levels of complexity for Pol III regulation, including substantial cell-type selectivity and intriguing overlap with Pol II transcription. Here I describe these novel insights and consider their implications and the questions that remain. © 2011 Macmillan Publishers Limited. All rights reserved.


Insall R.H.,Beatson Institute for Cancer Research
Nature Reviews Molecular Cell Biology | Year: 2010

Current descriptions of eukaryotic chemotaxis and cell movement focus on how extracellular signals (chemoattractants) cause new pseudopods to form. This 'signal-centred' approach is widely accepted but is derived mostly from special cases, particularly steep chemoattractant gradients. I propose a 'pseudopod-centred' explanation, whereby most pseudopods form themselves, without needing exogenous signals, and chemoattractants only bias internal pseudopod dynamics. This reinterpretation of recent data suggests that future research should focus on pseudopod mechanics, not signal processing. © 2010 Macmillan Publishers Limited. All rights reserved.

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