New tricks for an old-favorite model

A report of the 24th International Conference on Yeast Genetics and Molecular Biology, Manchester, UK, 19-24 July 2009

Developmental genomics reaches new heights

A report on the EMBO/SNF symposium 'The Genomics of Development', Arolla, Switzerland, 21-27 August 2006

T-box Genes in Limb Development and Disease

T-box genes comprise an ancient family of transcriptional regulators with important functions during development. The aim of this study is to investigate the roles of two closely related T-box genes Tbx5 and Tbx3 in limb development using the mouse and chick embryo as model organisms. These genes are physically linked in the genome, and human mutations in TbX5 and TbX3 lead to congenital diseases. Tbx5, is expressed in the forelimb but not in the hindlimb of the developing vertebrate embryo and has been proposed to have a role in limb-type specification. However, Tbx5 is also required for normal limb development since haploinsufficiency of TBX5 in human causes Holt-Oram Syndrome (HOS), a dominant disorder characterized by fore(upper) limb deformities and heart defects. I have taken two approaches to investigate the role of Tbx5 in limb- type specification and outgrowth. The first is a conditional knock-out method in the mouse where I inactivated Tbx5 specifically in the developing forelimbs. As a complementary strategy I injected dominant-negative and dominant-active forms of Tbx5 in the developing chicken wing using replication-competent avian retroviruses. My results from the mouse, suggest that Tbx5 has a vital role during early limb formation. In addition, my data using the chicken retroviral system establish a role for Tbx5 in later limb patterning events and provide an insight into understanding the genesis of HOS deformities in man

Cell signaling and cancer

A report on the Cancer Research UK London Research Institute Special Conference 'Signal Transduction', London, UK, 14-16 May 2007

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

Ageing is a complex trait controlled by genes and the environment. The highly conserved mechanistic target of rapamycin signalling pathway (mTOR) is a major regulator of lifespan in all eukaryotes and is thought to be mediating some of the effects of dietary restriction. mTOR is a rheostat of energy sensing diverse inputs such as amino acids, oxygen, hormones, and stress and regulates lifespan by tuning cellular functions such as gene expression, ribosome biogenesis, proteostasis, and mitochondrial metabolism. Deregulation of the mTOR signalling pathway is implicated in multiple age-related diseases such as cancer, neurodegeneration, and auto-immunity. In this review, we briefly summarise some of the workings of mTOR in lifespan and ageing through the processes of transcription, translation, autophagy, and metabolism. A good understanding of the pathway’s outputs and connectivity is paramount towards our ability for genetic and pharmacological interventions for healthy ageing and amelioration of age-related disease

Bright days for yeast research

A report on the British Yeast Group Meeting, Brighton, UK, 23-25 March 2011

Chickens get their place in the sun

A report on the International Chick Meeting 'The Chick as a Model Organism: Genes, Development and Function', Barcelona, Spain, 11-14 April 2007

Elucidating developmental gene networks

A report on the Joint Meeting of the British Societies for Cell and Developmental Biology, Warwick, UK, 31 March-3 April, 2008

Caffeine stabilises fission yeast Wee1 in a Rad24-dependent manner but attenuates its expression in response to DNA damage identifying a putative role for TORC1 in mediating its effects on cell cycle progression

The widely consumed neuroactive compound caffeine has generated much interest due to its ability to override the DNA damage and replication checkpoints. Previously Rad3 and its homologues was thought to be the target of caffeine’s inhibitory activity. Later findings indicate that the Target of Rapamycin Complex 1 (TORC1) is the preferred target of caffeine. Effective Cdc2 inhibition requires both the activation of the Wee1 kinase and inhibition of the Cdc25 phosphatase. The TORC1, DNA damage, and environmental stress response pathways all converge on Cdc25 and Wee1. We previously demonstrated that caffeine overrides DNA damage checkpoints by modulating Cdc25 stability. The effect of caffeine on cell cycle progression resembles that of TORC1 inhibition. Furthermore, caffeine activates the Sty1 regulated environmental stress response. Caffeine may thus modulate multiple signalling pathways that regulate Cdc25 and Wee1 levels, localisation and activity. Here we show that the activity of caffeine stabilises both Cdc25 and Wee1. The stabilising effect of caffeine and genotoxic agents on Wee1 was dependent on the Rad24 chaperone. Interestingly, caffeine inhibited the accumulation of Wee1 in response to DNA damage. Caffeine therefore modulates cell cycle progression contextually through increased Cdc25 activity and Wee1 repression following DNA damage via TORC1 inhibition

Caffeine Stabilises Fission Yeast Wee1 in a Rad24-Dependent Manner but Attenuates Its Expression in Response to DNA Damage

The widely consumed neuroactive compound caffeine has generated much interest due to its ability to override the DNA damage and replication checkpoints. Previously Rad3 and its homologues was thought to be the target of caffeine’s inhibitory activity. Later findings indicate that the Target of Rapamycin Complex 1 (TORC1) is the preferred target of caffeine. Effective Cdc2 inhibition requires both the activation of the Wee1 kinase and inhibition of the Cdc25 phosphatase. The TORC1, DNA damage, and environmental stress response pathways all converge on Cdc25 and Wee1. We previously demonstrated that caffeine overrides DNA damage checkpoints by modulating Cdc25 stability. The effect of caffeine on cell cycle progression resembles that of TORC1 inhibition. Furthermore, caffeine activates the Sty1 regulated environmental stress response. Caffeine may thus modulate multiple signalling pathways that regulate Cdc25 and Wee1 levels, localisation and activity. Here we show that the activity of caffeine stabilises both Cdc25 and Wee1. The stabilising effect of caffeine and genotoxic agents on Wee1 was dependent on the Rad24 chaperone. Interestingly, caffeine inhibited the accumulation of Wee1 in response to DNA damage. Caffeine may modulate cell cycle progression through increased Cdc25 activity and Wee1 repression following DNA damage via TORC1 inhibition, as TORC1 inhibition increased DNA damage sensitivity