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Proton pump inhibitors (PPIs) have off-target activity on fatty acid synthase (FASN), a critical enzyme in energy balance and cancer growth. We evaluated risk of common obesity-related cancers: breast, colorectal (CRC), and endometrial, with use of PPI and histamine-2 receptor antagonists (H2RA) in 124,931 postmenopausal women enrolled in the Women's Health Initiative. Incident cancer cases were physician-adjudicated. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for cancer incidence after year 3. There were 7956 PPI ever users and 9398 H2RA only users. Ever use of either PPI or H2RA was not associated with risk of breast cancer (n = 9186) nor risk of endometrial cancer (n = 1231). The risk of CRC (n = 2280) was significantly lower in PPI users (HR = 0.75, 95% CI = 0.61–0.92), but not in H2RA users (HR = 1.13, 95% CI = 0.97–1.31). The association of PPI use with CRC was apparent regardless of BMI or NSAID use, and was stronger with longer PPI duration (p = 0.006) and potency (p = 0.005). The findings that PPI use, but not H2RA use, demonstrate an inverse dose-response relationship with risk of CRC is consistent with preclinical data showing FASN inhibition prevents colon cancer progression and supports a role of PPI in CRC prevention. [ABSTRACT FROM AUTHOR]

Research has been conducted on the xeroderma pigmentosum group A. Results indicate that under normal conditions in solution xeroderma pigmentosum group A is a dimer in the free state or as a complex with human replication protein A.

Research has been conducted on the human multidrug resistance protein 1. The monoclonal antibody which is directed against the human multidrug resistance protein 1 amino terminus has been investigated in studying the putative extracellular amino terminus of this protein and the details are reported.

Two transmembrane (TM) segments of cystic fibrosis transmembrane conductance regulator (CFTR), namely, TM1 and TM2, exhibit correct membrane insertion and folding which play an important role in the membrane insertion and folding of the subsequent TM segments of CFTR. This is observed in an analysis of the topogenesis of TM3 and TM4 of CFTR in a cell-free expression system and the mechanism of regulation by the amino terminal transmembrane sequences. The correct membrane insertion of TM3 and TM4 is ensured by amino acid sequences that flank the two segments and regulated by the correct membrane insertion of their preceding TM1 and TM2.

Research was conducted to examine the mechanism underlying the generation of the various C-half Pgp topologies of Chinese hamster pgp1 Pgp. The membrane insertion characteristics of transmembrane (TM) topology were studied using the model protein in a cell-free system. Results indicate that the unique topogenic characteristics of TM8 direct the production of multiple C-half topological orientations.

Understanding of the topogenesis and membrane assembly of membrane proteins with multiple TM segments, remains incomplete. Several P-glycoprotein (Pgp) studies indicate that the topogenesis of polytopic membrane proteins is more complex that previously thought. A study of the mechanism by which Pgp topogenesis is determined, found that ribosomes are involved in the regulation of membrane insertion and folding of Pgp during translation. It is proposed that ribosomes or proteins linked with ribosomes can assist in reinitiation of internal TM insertion into the membrane.

P-glycoprotein (Pgp), a polytopic membrane protein, has an unconventional typology which represents its different functional state. The protein aids the multidrug resistance in cancer cell lines. Unlike the ATP-binding sites which are found in the cytoplasm, the loops linking TM4 and TM5 (loop 4) and the loop linking TM8 and TM9 (loop 8) are placed extracellularly. Proteolysis of Pgp is ordered as the trypsin-sensitive sites are cleaved in an organized way.

The mammalian polytopic membrane P-glycoprotein (Pgp) is regulated by amino acid sequence of protein and by soluble cytoplasmic components. The Pgp causes multidrug resistance by actively extruding cytotoxic agents out of cells. The Pgp expresses as rabbit reticulocyte lysate (RRL) and wheat germ extract (WGE) and functions as peptide transporter and as a chloride channel. The WGE regulate the membrane topology of truncated Pgp molecule.