Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscleinvasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

The underlying cause of neocortical involvement in temporal lobe epilepsy (TLE) remains a fundamental and unanswered question. Magnetic resonance imaging has shown a significant loss in temporal lobe volume, and it has been proposed that neocortical circuits are disturbed functionally because neurons are lost. The present study used design-based stereology to estimate the volume and cell number of Brodmann's area 38, a region commonly resected in anterior temporal lobectomy. Studies were conducted on the neocortex of patients with or without hippocampal sclerosis (HS). Results provide the surprising finding that TLE patients have significant atrophy of neocortical gray matter but no loss of neurons. Neurons are also significantly larger, dendritic trees appear sparser, and spine density is noticeably reduced in TLE specimens compared with controls. The increase in neuronal density we found in TLE patients is therefore attributable to large neurons occupying a much smaller volume than in normal brain. Neurons in the underlying white matter are also increased in size but, in contrast to other reports, are not significantly elevated in number or density. Neuronal hypertrophy affects HS and non-HS brains similarly. The reduction in neuropil and its associated elements therefore appears to be a primary feature of TLE, which is not secondary to cell loss. In both gray and white matter, neuronal hypertrophy means more perikaryal surface area is exposed for synaptic contacts and emerges as a hallmark of this disease. Key words: temporal lobe epilepsy; stereology; Brodmann's area 38; ectopia; cortical atrophy; neuronal hypertrophy; hippocampal sclerosisHippocampal sclerosis (HS) is the most frequently encountered pathologic abnormality in intractable epilepsy. There is however increasing evidence of more widespread temporal lobe pathology in HS patients (Nakasato et al., 1992;Sisodiya et al., 1995) and prevalent temporal lobe hypometabolism in patients with temporal lobe epilepsy (TLE) (Rausch et al., 1994). Moreover, magnetic resonance imaging (MRI) studies show a reduction in temporal lobe volume both ipsilateral and contralateral to the seizure focus (Lee et al., 1995Marsh et al., 1997). Volume reduction is also independent of the presence of HS (Sisodiya et al., 1997), which indicates that it underlies a broader spectrum than mesial temporal disease alone.Pathologic studies of TLE neocortex are dominated by those focused on readily detectable lesions and gross developmental abnormalities (Choi and Matthias, 1987;Haines et al., 1991;Raymond et al., 1995). There are far fewer investigations of subtle morphological abnormalities in the neocortex than in the hippocampus (Mathern et al., 1995), even though such studies might be expected to answer basic questions about epileptogenic activity originating outside the hippocampus and gross volume reductions in the temporal lobe.A common view of cortical pathology in TLE is that of neuronal loss. This notion is based on reports of reduced numbers of inhibitory neurons (DeFelip...

No abstract

No abstract