Research Highlights

Short, accessible synopses of recent important articles concerning signalling pathways.

May 2008

• Mechanisms of disease: Stress and disease connect at mTORC1

  

  Loss of the tuberous sclerosis complex (TSC) genes TSC1 and TSC2 leads to constitutive activation of the mammalian target of rapamycin complex-1 (mTORC1) and downstream signalling components, resulting in insulin resistance, the development of tumours and neurological disorders. Hotamisligil and colleagues now reveal a previously unrecognized connection between two important, highly conserved pathways — the mTORC1 and the endoplasmic reticulum (ER)-stress pathways — and demonstrate that the ER is wired to the mTOR pathway to control nutrient homeostasis, insulin action and survival.

  Original research paper Nature Reviews Molecular Cell Biology 9 349 doi:10.1038/nrm2396

• Signalling: Follow your eNOS

  

  The Achilles heel of many tumours is thought to be their 'addiction' to or dependence on specific factors and pathways, such as activation of the phosphatidylinositol 3-kinase (PI3K)- Akt signalling pathway in tumour cells expressing oncogenic Ras. But what is it about these factors that tumours can't live without? In Nature, Kian-Huat Lim et al. have identified endothelial nitric oxide synthase (eNOS or NOS3) as a target downstream of activated Ras and Akt that is required for tumour growth and maintenance.

  Original research paper Nature Reviews Cancer 8 322 - 323 doi:10.1038/nrc2382

• Signalling: An oncogene becomes RESTless

  

  REST (repressor-element-1 silencing transcription factor) is a transcriptional repressor that is associated with the maintainenance of neuron stem cell self-renewal and has been characterized as an oncogene in neuronal stem cells and, paradoxically, as a tumour suppressor in epithelial tissues. How REST accomplishes these activities and how it is incorporated into cell signalling pathways is unclear. Two papers published in Nature, from Westbrook and colleagues, and Guardavaccaro and colleagues, report a novel pathway linking REST to the ubiquitin-proteasome system and cell-cycle regulation with implications for this dual activity of REST.

  Original research paper Nature Reviews Cancer 8 327 doi:10.1038/nrc2378

• Molecular neuroscience: Stress hormones Trk neurons into survival

  

  Glucocorticoids have a bad reputation. However, although these stress hormones can be neurotoxic in high levels, they are also required for neuronal survival, and they promote neuronal growth and differentiation and support synaptic plasticity in the hippocampus. Chao and colleagues now show that, in rats, the neuroprotective effects of glucocorticoids are mediated by the activation of neurotrophin receptors.

  Original research paper Nature Reviews Neuroscience 9 328 - 329 doi:10.1038/nrn2382

• Inflammation: Stopping before the damage is done

  

  The activation of nuclear factor-κB (NF-κB) in response to cytokine signalling is a powerful mechanism for initiating an inflammatory immune response, but as is often the case in the immune system, with great power comes the potential to cause great damage. Li and colleagues now describe another element of the control systems that are responsible for preventing inflammatory damage to the host.

  Original research paper Nature Reviews Immunology 8 324 - 325 doi:10.1038/nri2324