PubMed · 4822703
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S Levey. 1974. Letter: Square bladder.. https://doi.org/10.1016/s0090-4295(74)80181-0
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The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the major rate-limiting enzyme in sterol and non-sterol isoprenoid synthesis. Isoprenoids are involved in the mechanisms of cell proliferation and transformation leading notably to crucial post-translational maturation of small G-proteins of the Ras superfamily. HMG-CoA reductase is among the most highly regulated enzymes. It is controlled by several feedback regulation mechanisms induced by sterol and non-sterol metabolites. The present results show that tyrosine kinase activity is also involved in the regulation of HMG-CoA reductase activity in the human breast cancer cell line SKBR-3. Incubation of SKBR-3 cells with the tyrosine kinase inhibitor, herbimycin A, induces a concentration-dependent reduction of HMG-CoA reductase activity with an IC50 of 80nM. The inhibition of HMG-CoA reductase activity by herbimycin A is also time-dependent. A similar effect of herbimycin A was obtained on the steady-state level of the HMG-CoA reductase protein. The effect of herbimycin A is probably specific as it abolished the stimulation of reductase activity by epidermal growth factor. To elucidate the molecular basis of the inhibition of HMG-CoA reductase activity and protein level by herbimycin A, we performed experiments to study the metabolic turnover of this enzyme using [35S]methionine and [35]cysteine. Herbimycin A (1 microM) did not have any significant effect on the rate of HMG-CoA reductase protein degradation but did affect its rate of synthesis and mRNA levels. The decrease in protein synthesis rate correlates with the lower reductase protein level but is more pronounced than the decrease in mRNA levels. Taken together, the results reveal a novel pathway of regulation of HMG-CoA reductase expression and activity by cellular tyrosine kinase activities.
Time trends in the incidence of cervical adenocarcinoma and adenosquamous cell carcinomas during the period 1973-1991 were examined using data provided by 60 population-based cancer registries from 32 defined populations in 25 countries. Three components of the incidence trend were studied: age, calendar period of diagnosis and birth cohort. Cumulative incidence rates per 1,000 for 2 groups with age ranges 25-49 and 50-74 years were calculated from the model that best described the incidence data. There was a significant increase in the cumulative incidence of cervical adenocarcinomas in women born in the mid-1930s and in successive cohorts thereafter in some populations in the United States (whites and Hispanic women), Australia, New Zealand (non-Maori), England, Scotland, Denmark, Slovenia, Slovakia and Japan (Osaka) and among Chinese women in Singapore, with a general decline in the incidence in women born in earlier periods. In Sweden and Slovenia there is a suggestion of an increasing trend in both age groups. A decrease in incidence in both age groups was apparent in Finland, France and Italy. There were no changes in incidence in 24 registries covering other European, Asian and black populations in the United States. Part of the increase may be attributable to an increasing prevalence of human papillomavirus infection, and part to improvements in screening.