Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc -/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.
The prevalence of cardiovascular risk factors, especially low level of high density lipoprotein cholesterol (HDL-C), is very high in Iran. The associations of apolipoprotein E (Apo E) polymorphism with lipid profile, especially high density lipoprotein (HDL) subfractions, were examined in Iranian population. A cross-sectional study of 1030 subjects (452 men and 578 women) from the Tehran Lipid and Glucose Study (TLGS) was performed. Serum triacylglycerol, cholesterol, FBS, HDL-C levels and its subfractions, Apo B and Apo A1 were determined and body mass index and blood pressure were measured. A segment of the mentioned gene was amplified by PCR and the polymorphisms were revealed by RFLP using HhaI restriction enzyme. Allele frequencies obtained for APOE Ã 2, APOE Ã 3, and APOE Ã 4 were 5.77, 85.92, and 8.3%, respectively. The presence of the e2 allele was significantly associated with increased serum HDL-C levels and its subfractions both in men and women except HDL3 in men. The LDL/HDL ratio was significantly lower in female. The relations were significant even after adjustment for age, sex, and BMI but hypertension, smoking, and diabetes status decreased the effect of Apo E2 on HDL-C and HDL subfractions. The observed genotype and allele frequencies were similar to those reported for other Caucasians samples. Apo E2 increased the level of HDL-C, HDL subfractions, and decreased the LDL/HDL ratio. These findings highlight the important effect of variation in this gene on lipid levels.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.