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Chronological life span is defined by how long a cell can survive in a non-dividing state. In yeast, it is measured by viability after entry into stationary phase. To date, some factors affecting chronological life span have been identified; however, the molecular details of how these factors regulate chronological life span have not yet been elucidated clearly. Because life span is a complicated phenomenon and is supposedly regulated by many factors, it is necessary to identify new factors affecting chronological life span to understand life span regulation. To this end, we have screened for long-lived mutants and identified Pma1, an essential P-type proton ATPase, as one of the determinants of chronological life span. We show that partial loss of Pma1 activity not only by mutations but also by treatment with the Pma1 inhibitory chemical vanadate resulted in the longlived phenotype in Schizosaccharomyces pombe. These findings suggest a novel way to manipulate chronological life span by modulating Pma1 as a molecular target.In the natural environment, most microorganisms exhibit only brief periods of rapid growth. Nutrient starvation is the most common natural situation, so the ability to adapt to nutrient limitation is crucial for microorganisms. Cells respond to starvation by ceasing growth and entering stationary phase and differentiate in ways that allow them to maintain viability for extended periods in the absence of nutrients (1). In yeast, the period in which the cells keep their viability after entry into stationary phase is recognized as the chronological life span (2).In Saccharomyces cerevisiae, two of the major pathways that control chronological life span have been identified: the Ras-PKA-Msn2/4 pathway and the Sch9 pathway (3, 4). The downregulation of either pathway promotes life span extension. Importantly, similar pathways (insulin/insulin-like growth factor I-like) regulate longevity in higher eukaryotes, suggesting a common evolutionary origin for the life span regulatory mechanisms (5, 6).In Schizosaccharomyces pombe, Pka1 and Sck2 are regulators of chronological life span; each mutant shows a long-lived phenotype, and the pka1 sck2 double mutant displays an additive effect on chronological life span extension, suggesting that these two factors regulate related but independent pathways (7). We reported previously that a mutant of lcf1 ϩ , which encodes a long-chain fatty acyl-CoA synthetase, showed rapid loss of viability after entry into stationary phase and suggested that fatty acid utilization and/or metabolism is important to determine viability in stationary phase in fission yeast (8,9). Recently, we identified a novel gene, ecl1 ϩ , which extends the chronological life span of S. pombe when overexpressed (10). In addition, we also identified two paralogs and one ortholog of ecl1 ϩ in S. pombe and S. cerevisiae, respectively (11, 12). On the basis of these observations, we proposed that Ecl1 family proteins are novel regulators for chronological life span in yeast. Ecl1 family proteins ...

Colorectal villous adenoma is thought to be associated with a high risk of progression to adenocarcinoma. To better characterize the genetic alterations involved in colorectal carcinogenesis related to villous adenoma, we analyzed mutations in APC, BRAF, KRAS, TP53, and GNAS in 12 colorectal adenocarcinomas associated with villous adenomas. APC, KRAS, and BRAF mutations were identified in five, 11, and one lesion, respectively, and most of these mutations were shared between the villous adenoma and the adenocarcinoma components in the respective lesions, except in one lesion with APC mutations and in two lesions with KRAS mutations. TP53 mutations were observed exclusively in four adenocarcinoma components, consistent with their role in the progression from adenoma to adenocarcinoma. Activating GNAS mutations were found in nine villous adenomas; however, unexpectedly, these mutations were shared only in three associated adenocarcinomas. Notably, all six adenocarcinomas with discordant GNAS mutation statuses were nonmucinous type, whereas all the other adenocarcinomas, including three adenocarcinomas associated with GNAS wild-type villous adenomas, were mucinous type. The current study suggests that GNAS-mutated villous adenomas may not necessarily be direct precursors of associated adenocarcinomas. At the same time, our observations support the role of activating GNAS mutations in increased mucin production in colorectal neoplasms.

An intriguing mutant was isolated in Schizosaccharomyces pombe, which is defective in the maintenance of viability after entry into the stationary phase. In the logarithmic growth phase, the mutant cells grow at the same rate as the parental cells. Upon the onset of the stationary phase, however, the mutant cells lose viability very rapidly. It was found that this phenotype was due to a mutational lesion in the lcf1+ gene, which encodes a long-chain fatty acyl-CoA synthetase. The lcf1Deltamutant shows pleiotropic phenotypes, in that they are also sensitive to high temperature (37 degrees C) and to high salt concentrations (0.9 M KCl) in the medium. Based on the fact that Lcf1 is highly homologous to Faa1 and Faa4 of Saccharomyces cerevisiae, both of which have previously been suggested to play roles in the maintenance of endogenous acyl-CoA pools, the possible function of Lcf1 in S. pombe is discussed.

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