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31.
32.
Ribiczey P Tordai A Andrikovics H Filoteo AG Penniston JT Enouf J Enyedi A Papp B Kovács T 《Cell calcium》2007,42(6):590-605
In this work we demonstrate a differentiation-induced up-regulation of the expression of plasma membrane Ca2+ATPase (PMCA) isoforms being present in various gastric/colon cancer cell types. We found PMCA1b as the major isoform in non-differentiated cancer cell lines, whereas the expression level of PMCA4b was significantly lower. Cell differentiation initiated with short chain fatty acids (SCFAs) and trichostatin A, or spontaneous differentiation of post-confluent cell cultures resulted in a marked induction of PMCA4b expression, while only moderately increased PMCA1b levels. Up-regulation of PMCA4b expression was demonstrated both at the protein and mRNA levels, and closely correlated with the induction of established differentiation markers. In contrast, the expression level of the Na+/K+-ATPase or that of the sarco/endoplasmic reticulum Ca2+ATPase 2 protein did not change significantly under these conditions. In membrane vesicles obtained from SCFA-treated gastric/colon cancer cells a marked increase in the PMCA-dependent Ca2+ transport activity was observed, indicating a general increase of PMCA function during the differentiation of these cancer cells. Because various PMCA isoforms display distinct functional characteristics, we suggest that up-regulated PMCA expression, together with a major switch in PMCA isoform pattern may significantly contribute to the differentiation of gastric/colon cancer cells. The analysis of PMCA expression may provide a new diagnostic tool for monitoring the tumor phenotype. 相似文献
33.
Phylogenetic distribution of catalase-peroxidases: are there patches of order in chaos? 总被引:1,自引:0,他引:1
Hydrogen peroxide features in many biological oxidative processes and must be continuously degraded enzymatically either via a catalatic or a peroxidatic mechanism. For this purpose ancestral bacteria evolved a battery of different heme and non-heme enzymes, among which heme-containing catalase-peroxidases (CP) are one of the most widespread representatives. They are unique since they can follow both H(2)O(2)-degrading mechanisms, the catalase activity being clearly dominant. With the fast increasing amount of genomic data available, we were able to perform an extensive search for CP and found almost 300 sequences covering a large range of microorganisms. Most of them were encoded by bacterial genomes, but we could also find some in eukaryotic organisms other than fungi, which has never been shown until now. Our screen also reveals that approximately 60% of the bacteria do not possess CP genes. Chaotic distribution among species and incongruous phylogenetic reconstruction indicated existence of numerous lateral gene transfers in addition to duplication events and regular speciation. The results obtained show an impressively complex gene transmission pattern, and give some new insights about the role of CP and the origin of life on earth. Finally, we propose for the first time bacterial candidates that may have participated in the transfer of CP from bacteria to eukaryotes. 相似文献
34.
Charafe-Jauffret E Chaffanet M Bertucci F Ginestier C Jacquemier J deLapeyrière O Birnbaum D 《Médecine sciences : M/S》2007,23(6-7):626-632
Breast cancer is a major health problem as well as scientifically poorly understood. Our knowledge of breast cancer is however rapidly progressing in several directions. First, genomic studies are establishing a new molecular classification of breast cancers. Molecular subtypes have been identified and are being associated with the histoclinical forms of breast cancers. Second, genetic alterations are discovered and classified, generating new potential therapeutical targets. Third, mammary stem cells have been identified in the normal mammary epithelium. Their altered counterparts have been identified in tumors and are being characterized. These combined studies allow a new integrated cellular and molecular definition of breast cancers and a conceptual basis that will help the management of the disease. 相似文献
35.
Powell DA Black WC Bleasby K Chan CC Deschenes D Gagnon M Gordon R Guay J Guiral S Hafey MJ Huang Z Isabel E Leblanc Y Styhler A Xu LJ Zhang L Oballa RM 《Bioorganic & medicinal chemistry letters》2011,21(24):7281-7286
An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity. 相似文献
36.
Isabel E Powell DA Black WC Chan CC Crane S Gordon R Guay J Guiral S Huang Z Robichaud J Skorey K Tawa P Xu L Zhang L Oballa R 《Bioorganic & medicinal chemistry letters》2011,21(1):479-483
Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared. 相似文献
37.
Ramtohul YK Powell D Leclerc JP Leger S Oballa R Black C Isabel E Li CS Crane S Robichaud J Guay J Guiral S Zhang L Huang Z 《Bioorganic & medicinal chemistry letters》2011,21(19):5692-5696
Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors. 相似文献
38.
39.
Giraud A Dicristofaro J De Micco C Lejeune PJ Barbaria J Mallet B 《Biochemical and biophysical research communications》2005,338(2):1000-1004
The prothyroid hormone, thyroglobulin (Tg), is stored at high concentrations in the thyroid follicular lumen as a soluble 19S homo-dimer and as heavier soluble (27S and 37S) and insoluble (Tgm) forms. Follicular degradation of Tg may contribute to maintaining Tg concentrations compatible with follicle integrity. Here, we report on the presence of a plasminogen-like protein in the follicular lumen of normal human thyroids and its synthesis and apical secretion by cultured epithelial thyroid cells. Since all the main luminal forms of Tg are cleaved by this plasminogen-like protein, we suggest that it contributes to Tg degradation in the follicular lumen. 相似文献
40.