Arsenite regulates Cystic Fibrosis Transmembrane Conductance Regulator and P-glycoprotein: evidence of pathway independence.
In the past, people have argued for and against the theory of reciprocal regulation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and P-glycoprotein (Pgp). Data have indicated that this may occur in vitro during drug-induced selection of cells, and in vivo during development. Much of this debate has been caused by a severe lack of mechanistic details involved in such regulation. Our past data indicate that certain Pgp modulators can affect CFTR expression and function. The goal of this study was to investigate the effects of trivalent arsenic (arsenite), a known transcriptional activator of Pgp, on CFTR expression. In vitro analyses in T-84 cells that express basal levels of Pgp and CFTR were conducted using a variety of molecular techniques. Expressions of both genes were altered following treatment with arsenite in a dose- and time-dependent fashion. CFTR expression was suppressed almost three-fold by arsenite, along with a concomitant increase in P-glycoprotein expression. We also report that a member of the MAPK-family, the ERK-mediated signaling cascade is implicated in suppression of CFTR expression following treatment with arsenite. However, this particular pathway is not involved in regulation of P-glycoprotein expression in T-84 cells following treatment with arsenite. Thus, the regulatory pathways that control functional expression of CFTR and P-glycoprotein following arsenite treatment in T-84 cells are distinct and independent.
Maitra
Rangan
R
Department of Pharmacology and Toxicology, Dartmouth Medical School Hanover, NH 03755-3835, USA.
Hamilton
Joshua W
JW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D018053:Arsenites / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018053:Arsenites; C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C015001:arsenite