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Port Glasgow, United Kingdom

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. Source

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. Source

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. Source

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. Source

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. Source

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