Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two independent lines of experimental evidence are presented in support of the hypothesis that senescence is a normal mechanism of tumor suppression, a homeostatic device designed through evolution to limit cell proliferation irreversibly and thereby to protect the organism against cancer. One set of experiments uses normal human foreskin fibroblasts, transfected at early passage with SV40 DNA and subsequently infected with the K-ras virus. If the cells are immortal prior to infection, they become tumorigenic and make large tumors in nude mice, whereas if they are not immortal, though expressing SV40 T-antigen, they make tiny tumors that senesce in the test mouse after as many doublings as similar cells make in culture. This result demonstrates that immortalization is essential for progressive tumor growth in vivo. The second set of experiments demonstrate that normal human mammary epithelial cells can be immortalized by transfection with viral DNA from human papilloma virus 16 or 18, although these viruses have not been associated with breast cancer. The effective immortalization and other premalignant changes induced by human papilloma virus transfection are accompanied by chromosome changes that may contribute to the partially transformed phenotypes. None of the cloned or pooled transfectants have been tumorigenic in the nude mouse assay. Here, too, immortalization is experimentally separable from tumor-forming ability.
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PMID:Senescence as a mode of tumor suppression. 166 51

SV40 T-antigen-expressing human cells generally have an extension of lifespan until a period called "crisis" begins. On rare occasions a clone of cells emerges from the population in crisis and gives rise to an immortalized cell line. The present study compares the frequency of immortalization of cells from two different human lineages, lung fibroblasts and mammary epithelial cells. Most of the T-antigen-transfected clones from both cell types failed to immortalize, however, within those clones which were immortalization-competent the frequency of escape from crisis was found to be much higher (10(-5)) in mammary epithelial cells than in human fibroblasts (3 x 10(-7)). The frequency of escape from crisis in fibroblasts could be increased by chemical mutagenesis or by infection with a defective retrovirus. T-antigen-transfected fibroblasts were uniformly highly aneuploid both before and after crisis. In contrast, many SV40 T-antigen- and human papilloma virus 16 E6- or E6/E7-transfected mammary epithelial clones maintained a subpopulation of pseudodiploid cells prior to crisis, and the immortal cells that emerged following crisis were generally pseudodiploid. The higher frequency of escape from crisis in mammary epithelial cells is best explained by postulating a mutational inactivation of one allele of a critical gene followed by the elimination of the remaining wild-type alleles, with a much higher frequency of this second event in mammary epithelial cells due to their reduced ploidy compared to that in T-antigen-transfected fibroblasts. The results are discussed in terms of the regulation of telomerase activity and the M1/M2 model of cellular senescence.
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PMID:The frequency of immortalization of human fibroblasts and mammary epithelial cells transfected with SV40 large T-antigen. 822 5

E6/E7 genes of human papilloma virus type 16 were used to immortalize a primary culture of marginal cells (MC) from gerbils. One of the cloned lines was selected which demonstrated preservation of the main characteristics of the MC, both morphologically and physiologically. Electron microscopic examination showed well-developed junctional complexes and apical microvilli which suggested its epithelial origin. Polymerase chain reaction (PCR) demonstrated the incorporation of E6/E7 genes with the genome. Reverse transcription PCR revealed the existence of mRNA of the IsK channel, a unique marker of MC among the inner ear cells, in this clone. Flow cytometric analysis of this cell line's DNA content was diploid. Numerous large domes formed after confluence of the cell monolayer. Electrophysiologic studies displayed evidence of apical K+ and Na+ channels which were blocked by Ba2+ (2 mM) and amiloride (10(-5) M), respectively. Existence of basolateral Na,K-ATPase and Na+/Cl-/K+ cotransporter was shown by blockage by ouabain (10(-3) M) and bumetanide (50 microM), individually. Injection of the cell line to nude mice failed to induce growth of tumors. This cell line was serum-, density- and anchorage-dependent when cultured in plastic dishes. In conclusion, this cell line shows characteristics of well-differentiated MC maintaining the major ionic transport processes, and provides us a good model to study the possible mechanisms and regulating factors of endolymph production.
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PMID:Establishment and characterization of a strial marginal cell line maintaining vectorial electrolyte transport. 974 59

In this study, we explored the protective anti-tumor potency of mouse (self) Hsp70 or Hsp110-based DNA vaccination approach targeting a tumor-associated antigen, human papilloma virus (HPV) type 16 E7 protein. Linkage of E7 to the N-terminus of the mouse Hsp70 not only elicits an E7-specific cytotoxic T cell (CTL) response, but also protects mice against challenge with E7 expressing tumors. CD8+ T-cells are crucial in both priming and effector phases for the induction of tumor immunity, whereas CD4+ T-cells and NK cells do not appear to play a major role. Furthermore, the ATP-binding domain deletion mutant Hsp70(382-641), when fused to E7, was immunologically effective, suggesting that the peptide-binding region, not the ATPase domain of Hsp70, is required for the vaccine activity of the E7-Hsp70 DNA. This study demonstrates that autologous Hsp70 is highly potent in enhancing antigen-specific immune responses. Functional domain mapping and orientation of the E7 and Hsp70 in the fusion gene may have clinical implications for the design and optimization of Hsp70-based DNA vaccines.
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PMID:Generation of anti-tumor immunity using mammalian heat shock protein 70 DNA vaccines for cancer immunotherapy. 1671 72