👤 John F Marshall

Oncogenic transformation often leads to the disruption of the actin cytoskeleton. Activation of the classical Ras-Raf-MEK1/2-ERK1/2 signalling cascade has been implicated in the effects of oncogenes such as Ras and Src on the cytoskeleton. Many of the studies of the effects of oncogenes on the cytoskeleton have made use of chemical inhibitors of MEK1/2 but it is now clear that these inhibitors also inactivate MEK5 in the MEK5-ERK5 MAP kinase pathway raising the possibility that this pathway may also be involved in oncogenic transformation. We therefore investigated whether activation of ERK5 can lead to disruption of the actin cytoskeleton. We show that activation of ERK5 can lead to loss of actin stress fibres, but by a distinct mechanism to ERK1/2. We demonstrate that ERK5 is activated by oncogenic Src as demonstrated by translocation of endogenous ERK5 from the cytoplasm to nucleus and activation of an ERK5-dependent transcriptional reporter and that ERK5 activation is required for Src-mediated transformation. We also show that in Src-transformed cells inhibition of ERK1/2 signalling is not sufficient for reappearance of the actin cytoskeleton and that ERK5 activation contributes to cytoskeletal disruption by Src. Our results suggest that multiple MAP kinase pathways downstream of oncogenes participate in cytoskeletal alterations. Show less

The activity of telomerase, an enzyme that synthesizes telomeric repeats at the ends of chromosomes, is not detectable in normal human prostate. However, the majority of human prostate cancers exhibit telomerase activity. Since androgens play a major role in prostate tumorigenesis, we investigated the effect of androgen-depletion on the expression of telomerase activity in the prostate. Adult male rhesus monkeys were either bilaterally castrated or subjected to sham surgery (n = 5 each). Approximately 6 weeks later, the animals were killed and the different regions of the prostate gland were removed and frozen immediately. Telomerase activity was assayed using the telomeric repeat amplification protocol. All five regions of the prostate from sham operated control animals failed to exhibit telomerase activity. In the castrated monkey, all regions of the prostate, except for the anterior lobe, expressed high levels of telomerase activity. Our results indicate that in monkeys, androgen-ablation leads to up-regulation of telomerase activity. The negative-regulation of telomerase activity by androgens is probably lost during prostate tumorigenesis. Show less

To determine whether there are any deleterious changes in the human testis after vasectomy, we obtained testicular biopsy specimens from 31 healthy men undergoing vasectomy reversal and from 21 healthy, fertile volunteers. Morphometric analyses of these specimens revealed a 100 per cent increase in the thickness of the seminiferous tubular walls (P less than 0.001), a 50 per cent increase in the mean cross-sectional tubular area (P less than 0.001), and a significant reduction in the mean number of Sertoli cells (P less than 0.01) and spermatids (P less than 0.01) per tubular cross section in the post-vasectomy group, as compared with the control group. Focal interstitial fibrosis was observed in 23 per cent of the specimens from the post-vasectomy group and in none from the control group. There was a significant correlation (P less than 0.01) between interstitial fibrosis and infertility in patients who underwent a surgically successful vasectomy reversal (sperm in the ejaculate). None of the other measured characteristics correlated with infertility after vasectomy reversal. We conclude that significant morphologic changes occur in the human testis after vasectomy. The presence of focal interstitial fibrosis was associated with a high incidence of infertility in this series. Show less