The Identification of the CF (Cystic Fibrosis) Gene: Recent by Robert Williamson (auth.), Lap-Chee Tsui, Prof. Giovanni

By Robert Williamson (auth.), Lap-Chee Tsui, Prof. Giovanni Romeo, Rainer Greger, Sergio Gorini (eds.)

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49. 50. 51. daunomycin binding to P-glycoprotein-containing membranes of multidrug-resistant Chinese hamster ovary cells, Eur. J. , 183:189 (1989). L. Slater, P. Sweet, M. Stupecky and S. Gupta, Cyclosporin A reverses vincristine and daunomycin resistance in acute lymphatic leukemia in vitro, J. Clin. , 77:1405 (1986). P. McGrath and A. Varshavsky, The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein, Nature, 340:400 (1989). K. E. Sterme and J. Thorner, Saccharomyces cerevisiae STE6 gene product: a novel pathway for protein export in eukaryotic cells, EMJO Journal, 8:3973 (1989).

The basis of their ability to transport compounds with different chemical structures is not well understood, but many of these compounds have been shown to bind specifically to the protein (32-35). Hence, despite some efforts to detect them, associated substrate-binding components of the type which provide specificity to the periplasmic uptake systems have not been observed. Similarly, there is, at least as yet, no evidence of additional membrane-associated molecules of the type exemplified by hemolysin D which contributes to the active export of substrates.

Only the Na pump enzyme can be absolutely excluded as not being equivalent to CFTR since its primary structure is known (42). However, features of the predicted CFTR structure would not be expected of either the cotransporter or the channel; for example, neither exhibits apparent sensitivity to ATP. Therefore, for CFTR to be directly involved in ion pumping, it presumably would have to serve a secondary role not recognized in the physiological studies on which the model is based. This could be the case, as it is clear that CFTR is strongly expressed in at least some of the principle tissues in which those studies were performed, such as the shark rectal gland (see below).

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