Regulation Of Brn-3a N-terminal transcriptional activity by MEK1/2-ERK1/2 signalling in neural differentiation

The POU family transcription factor Brn-3a is required for the differentiation and survival of sensory neurones, and is phosphorylated in neuroblastoma cells following treatment with all-trans retinoic acid (RA). Mutation of serines-121 and -122 of Brn-3a to alanine blocks its phosphorylation and impairs RA-mediated neurite outgrowth. Here we show that this deficit in differentiation is mimicked by a single mutation at serine-122, and demonstrate a similar requirement for a second residue, threonine-39. Like Brn-3a, the neuropeptide Galanin has been implicated in the development of sensory neurones. We show that Brn-3a over-expression acts synergistically with RA treatment to up-regulate Galanin promoter activity; that the activity of the N-terminal transcriptional activation domain of Brn-3a is increased following RA treatment; and that both these effects require threonine-39 and serine-122. In addition, we demonstrate that the RA-mediated activation of Galanin promoter activity and Brn-3a N-terminal transcriptional activity are both blocked by pan-MEK inhibitors, and show that the expression of a constitutively-active mutant of MEK1, but not MEK5, is sufficient to increase Brn-3a activity. These results reveal an important role for the ERK1/2 pathway in Brn-3a regulation during RA-mediated neuronal differentiation and define the neuropeptide Galanin as a novel target of this transcription factor

‘I am not someone who gets skin cancer’: Risk, time and malignant melanoma

‘Delay’ is a term used in the cancer literature since the 1930s to describe the period between self-detection of a concerning sign of possible disease and presentation to a health professional. This linguistic choice carries an implication of blame for apparent failure to manage a risk appropriately, drawing attention away from the contemporaneous perspectives of those who respond to suspicious indicators more or less quickly. We present findings from a grounded theory study of accounts given by 45 patients about their slower or quicker journeys to a diagnosis of cutaneous malignant melanoma, a cancer which can ‘hide in plain sight’. There has been little research exploring in qualitative detail patients’ perspectives on their decision-making about what subsequently turn out to have been signs of this most risky of skin cancers. The findings frame referral time-lapses in terms of normalisation of symptoms, sometimes buttressed by reassurance derived from health promotion messages, disconfirmation of patients’ concerns by their general practitioners and prioritisation of other life concerns. We argue that a shared sense of urgency surrounding melanoma self-referral derives from a clinical representation of current knowledge which conceals numerous evidential uncertainties