Murine colonic mucosa hyperproliferation. I. Elevated CFTR expression and enhanced cAMP-dependent Cl- secretion

Fluid transport in the large intestine is mediated by the cystic fibrosis g ene product and cAMP-dependent anion channel cystic fibrosis transmembrane conductance regulator (CFTR). cAMP-mediated Cl- secretion by gastrointestin al cell lines in vitro has been positively correlated with the insertion of CFTR into the apical membrane of differentiated senescent colonocytes and negatively correlated with the failure of CFTR to insert into the plasma me mbrane of their undifferentiated proliferating counterparts. In native tiss ues, this relationship remains unresolved. We demonstrate, in a transmissib le murine colonic hyperplasia (TMCH) model, that (8-fold) colonocyte prolif eration was accompanied by increased cellular CFTR mRNA and protein express ion (8.3- and 2.4-fold, respectively) and enhanced mucosal cAMP-dependent C l- secretion (2.3-fold). By immunofluorescence microscopy, cellular CFTR ex pression was restricted to the apical pole of cells at the base of the epit helial crypt. In contrast, increased cellular proliferation in vivo led to increases in both the cellular level and the total number of cells expressi ng this anion channel, with cellular CFTR staining extending into the crypt neck region. Hyperproliferating colonocytes accumulated large amounts of C FTR in apically oriented subcellular perinuclear compartments. This novel m ode of CFTR regulation may explain why high endogenous levels of cellular C FTR mRNA and protein within the TMCH epithelium were not matched with large r increases in transmucosal CFTR Cl- current.