Polycystin-1 transforms the cAMP growth-responsive phenotype of M-1 cells

Background. Polycystic kidney disease (PKD) is characterized by the abnorma l proliferation of tubular epithelial cells. It was recently shown that the growth of PKD cyst-lining cells is stimulated by cyclic adenosine monophos phate (cAMP), whereas the growth of normal human kidney cortex cells is inh ibited. Methods. We have examined the effects of overexpressing the C-terminal cyto solic tail of mouse polycystin-1, as a membrane-targeted fusion protein, on cAMP-responsive cell proliferation in stably transfected M-l cortical coll ecting duct cells. Two cell lines that express high levels of the polycysti n-1 fusion protein and two control cell lines that do not express the fusio n protein were tested. Results. Growth of parental M-l cells and the control cell lines was inhibi ted by 8-Br-cAMP and by a variety of cAMP agonists. In contrast: growth of the polycystin-1-expressing clones was stimulated by cAMP. Consistent with this. the protein kinase A (PKA) inhibitor H-89 caused either a positive or a negative growth effect depending on the primary response to cAMP. PD9805 9 blocked the cAMP stimulation of cell proliferation, indicating that the p athway is MEK1 dependent. Conclusions. Expression of the polycystin-1 C-terminal tail disrupts normal cellular signaling and transforms the stably transfected M-l cells to an a bnormal PKD cell proliferation phenotype.