Elevated glucocorticoid receptor transactivation and down-regulation of alpha 1 integrin are associated with loss of plasma membrane Ca2+-ATPase isoform 1.
We have previously shown that inhibition of expression of the plasma membrane Ca(2+)-ATPase isoform 1 in PC6 cells leads to loss of nerve growth factor-mediated neurite extension (Brandt, P.C., Sisken, J.E., Neve, R.L., and Vanaman, T.C. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 13843-13848). Cells lacking plasma membrane Ca(2+)-ATPase 1 did not attach to collagen-coated plates as tightly as controls, suggesting that a defect in adhesion might be underlying the inability to extend neurites. We report here that cell lines lacking plasma membrane Ca(2+)-ATPase 1 do not produce alpha(1) integrin, which is required for both collagen adherence and neurite extension. Because alpha(1) integrin gene transcription can be down-regulated by glucocorticoids, the response of cells to glucocorticoids was investigated. Cortisol-dependent transactivation from the mouse mammary tumor virus promoter in cells lacking plasma membrane Ca(2+)-ATPase 1 was stimulated 145-216-fold over untreated cells compared with 15-26-fold for controls. This increase was not due to increased binding affinity of the receptor for cortisol, an increased number of cortisol-binding sites, or increased translocation of the receptor to the nucleus. Expression of additional glucocorticoid receptor-dependent genes required for neurite extension must also be altered in cells missing the plasma membrane Ca(2+)-ATPase 1 because constitutive expression of alpha(1) integrin did not restore their nerve growth factor-mediated neurite extension capability. The impact of plasma membrane Ca(2+)-ATPase isoform 1 on other signaling systems and the resultant profound yet subtle effects on PC6 cells strongly suggests that it plays an important role in modulating signal transduction pathways downstream of Ca(2+)-mediated signals.
Brandt
P C
PC
Department of Medical Pharmacology and Toxicology, Texas A & M System Health Science Center, College Station, Texas 77843-1114, USA. pbrandt@medicine.tamu.edu
Vanaman
T C
TC
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins; D002462:Cell Membrane / Q000201:enzymology; D002467:Cell Nucleus / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006854:Hydrocortisone / Q000494:pharmacology; D039423:Integrin alpha1; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D016716:PC12 Cells; D053499:Plasma Membrane Calcium-Transporting ATPases; D011401:Promoter Regions, Genetic; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014221:Triamcinolone / Q000493:pharmacokinetics
D015703:Antigens, CD; D027682:Cation Transport Proteins; D039423:Integrin alpha1; D007527:Isoenzymes; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D014221:Triamcinolone; D053499:Plasma Membrane Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D006854:Hydrocortisone