Robert Campbell

Tumour necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function

Oestrogen receptor alpha (ERα) is an oestrogen-activated transcription factor, which regulates proliferation and differentiation of mammary epithelial cells by activating or repressing gene expression. ERα is a critical prognostic indicator and a therapeutic target for breast cancer. Patients with tumours that express higher level of ERα have better prognosis than patients with tumours that are ERα negative or express lower level of ERα. Better prognosis in ERα-positive patients is believed to be due to repression of proinvasive gene expression by ERα. Oestrogen receptor alpha represses gene expression by transrepressing the activity of the transcription factors such as nuclear factor-kappaB or by inducing the expression of transcriptional suppressors such as MTA3. In this report, we show that ERα transrepresses the expression of the proinvasive gene interleukin 6 (IL-6) in ERα-negative MDA-MB-231 breast cancer cells stably overexpressing ERα. Using these cells as well as ERα-positive MCF-7 and ZR-75-1 cells, we show that tumour necrosis factor alpha (TNFα) and the phosphatidylinositol-3-kinase (PI3-kinase) modulate transrepression function of ERα by reducing its stability. From these results, we propose that TNFα expression or PI3-kinase activation lead to reduced levels of ERα protein in cancer cells and corresponding loss of transrepression function and acquisition of an invasive phenotype.

Glycine and experimental spinal spasticity

Spasticity may result in part from segmental spinal disinhibition. We determined the content and specific activity of glycine (the putative neurotransmitter thought to mediate spinal postsynaptic inhibition) and serine (the probable precursor of glycine) in feline spastic spinal cord following the intra-aortic administration of two labelled precursors of glycine—14C-D-glucose and 14C-L-serine. The specific activities of both glycine and serine were significantly reduced in the ventromedial, central, and dorsal spinal gray matter in spastic animals. Glycine content remained at control values but serine content increased in spastic spinal cord. This study suggests that glycine turnover decreases in spasticity, owing to its diminished release, and supports neurophysiologic evidence of a decrement in postsynaptic inhibition.

A Study of Experimental Syringomyelia by Scanning Electron Microscopy

Experimental hydromyelia and syringomyelia, induced by kaolin in dogs, has been investigated by scanning electron microscopy. This study demonstrated that communication between the 4th ventricle and the spinal central canal is normally occluded by a plug of acellular material lying within the central canal. This plug is broken down following the onset of hydrocephalus and communication is rapidly established between the ventricles and the central canal. The canal distends and ruptures dorsally into the spinal gray matter with the development of extensive intramedullary cavities, lined by glial and neuronal elements. The morphological changes demonstrated are consistent with a physical destructive process of the cord resulting from CSF dissection.