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4.3 - 19th October 1998


Senescence marker protein-30 (SMP30) rescues cell death by enhancing plasma membrane Ca(2+)-pumping activity in Hep G2 cells.

Fujita T, Inoue H, Kitamura T, Sato N, Shimosawa T, Maruyama N

Department of Molecular Pathology, Tokyo Metropolitan Institute of Gerontology, Japan.

Biochem Biophys Res Commun 1998 Sep 18;250(2):374-80

Senescence marker protein-30 (SMP30) has been reported to decrease with aging in the rat liver. SMP30 has been also suggested to play a role as a Ca(2+)-binding protein localized in cytosol of hepatocytes. To elucidate the functional significance of SMP30, we have generated Hep G2 cell lines that stably express large amounts of SMP30 by transfection with human SMP30 cDNA. Using these cell lines, in view of the intracellular Ca2+ homeostasis, we then investigated cytosolic free Ca2+ concentration ([Ca2+]i) and Na(+)-independent Ca2+ efflux from the cells after extracellular ATP stimulation. Although stimulation of cells with ATP caused transient [Ca2+]i increase in both SMP30 and mock transfectants, rate of decrease after peak in [Ca2+]i was enhanced 2-fold by transfection of SMP30. Correspondingly, Ca2+ efflux was significantly increased in SMP30 transfectants compared with mock transfectants. In addition, more SMP30 transfectants survived than mock transfectants when cell death was induced by Ca2+ ionophore treatment. These results suggest that SMP30 regulates [Ca2+]i by modulating plasma membrane Ca(2+)-pumping activity, and thus down-regulation of SMP30 during aging may contribute to deterioration of cellular functions.

Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats.

Nitahara JA, Cheng W, Liu Y, Li B, Leri A, Li P, Mogul D, Gambert SR, Kajstura J, Anversa P

Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA.

J Mol Cell Cardiol 1998 Mar;30(3):519-35

Myocyte apoptosis increases with age in Fischer 344 rats, but the multiple molecular events implicated in this phenomenon remain to be identified. Several defects involving Ca2+ homeostasis, pH, and the expression of p53 and genes of the Bcl-2 protein family may contribute to the activation of myocyte death. Therefore, changes in intracellular pH, cytosolic Ca2+, DNase I and DNase II were measured in myocytes isolated by enzymatic digestion from rats of different ages. Moreover, the expression of p53, Bcl-2 and Bax in these cells was determined. Measurements of intracellular pH by BCECF fluorescence at 3, 12 and 24 months showed that this parameter did not change with age: 3 months, 7.20+/-0.05; 12 months, 7.21+/-0.07; 24 months, 7.18+/-0.09. In contrast, diastolic Ca2+ determined by the Fura 2-AM method increased progressively from 99.8+/-1.9 nm at 3 months to 136.3+/-9.6 nm at 24 months (P<0.001). Concurrently, DNase I activity evaluated by plasmid digestion assay in myocytes increased 3.2-fold from 3 to 24 months (P<0.02). Conversely, pH-dependent-DNase II remained essentially constant with age. Western blotting performed on ventricular myocytes did not detect significant changes in p53, Bax and Bcl-2 proteins with age. Similarly, immunocytochemically, the fraction of myocytes labeled by p53, Bax and Bcl-2 did not change from 3 to 24 months. In conclusion, myocyte aging is characterized by an increase in diastolic calcium which may activate DNase I triggering apoptosis, independently from the expression of p53, Bax and Bcl-2 in the cells.

Age at natural menopause and mortality.

Cooper GS, Sandler DP

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.

Ann Epidemiol 1998 May;8(4):229-35

PURPOSE: The purpose of this study was to examine the association between age at menopause and mortality in a population-based sample of women in the United States. METHODS: This study was based on data from the National Health and Examination Survey (NHANES) Epidemiologic Follow-up Study; 3191 women aged 50-86 years were included. There were 345 deaths over a mean follow-up time of 4.0 years. We used age-stratified and Poisson regression procedures to assess mortality risk by age at natural menopause, with adjustment for age, duration of follow-up, race, education, smoking, and use of hormone replacement therapy. We conducted a separate analysis for surgical menopause with bilateral oophorectomy. RESULTS: Compared with women who were menstruating to age 50 or later, the adjusted mortality rate ratios (RR) were 1.50 (95% confidence interval (CI), 0.97-2.34) for women with a natural menopause at age < 40, 1.04 (95% CI, 0.72-1.51) for those with menopause at age 40-44, and 0.96 (95% CI, 0.72-1.26) for those with menopause at age 45-49. Women with a natural menopause at age 40-44 years experienced an increased risk of cancer-related mortality (adjusted RR 2.34, 95% CI, 1.20-4.58). No age-related increased mortality risk was seen among women who had surgical menopause with bilateral oophorectomy. CONCLUSIONS: This study provides some support for the concept that age at natural menopause serves as a biological marker of health and aging, with potential implications extending beyond cardiovascular diseases.

Overcoming cellular senescence in human cancer pathogenesis.

Yeager TR, DeVries S, Jarrard DF, Kao C, Nakada SY, Moon TD, Bruskewitz R, Stadler WM, Meisner LF, Gilchrist KW, Newton MA, Waldman FM, Reznikoff CA

Department of Human Oncology, University of Wisconsin Medical School, Madison, Wisconsin 53792 USA.

Genes Dev 1998 Jan 15;12(2):163-74

Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC). Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG. In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and -3p. These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro. Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers. We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs. In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0.001). Comparative genomic hybridization (CGH) was used to identify regions of chromosome loss or gain in all TCC samples. The application of a statistical model to the CGH data showed a high probability of elevated alteration rates of +20q11-q12 (0.99) and +8p22-pter (0.94) in the immortal muscle invasive TCCs, and of -9q (0.99) in the superficial TCCs. Three myoinvasive TCCs lost 3p13-p14. In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized. Notably, TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0.04) than was p16 or pRb alteration (P = 0.001). Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11-q12, -3p13-p14, or -8p21-pter.



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