Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1.
Arginine vasopressin (AVP), a vasoactive peptide hormone that binds to three G-protein coupled receptors (V1R, V2R, and V3R), has long been known to activate V1R and elicit mitogenesis in several cell types, including adrenal glomerulosa cells. However, in the mouse Y1 adrenocortical malignant cell line, AVP triggers not only a canonical mitogenic response but also novel RhoA-GTP-dependent mechanisms which downregulate cyclin D1, irreversibly inhibiting K-ras oncogene-driven proliferation. In Y1 cells, AVP blocks cyclin D1 expression, induces senescence-associated beta-galactosidase (SAbeta-Gal) and inhibits proliferation. However, ectopic expression of cyclin D1 renders Y1 cells resistant to both SAbeta-Gal induction and proliferation inhibition by AVP. In addition, ectopic expression of the dominant negative RhoAN19 mutant blocks RhoA activation, yielding Y1 cell sub-lines which are no longer susceptible to cyclin D1 downregulation, SAbeta-Gal induction, or proliferation inhibition by AVP. Furthermore, inhibiting RhoA with C3 exoenzyme protects Y1 cells from AVP proliferation inhibition and SAbeta-Gal induction. On the other hand, AVP treatment does not activate caspases 3 and 7, and the caspase inhibitor Ac-DEVD-CMK does not protect Y1 cells from proliferation inhibition by AVP, implying that AVP does not trigger apoptosis. These results underline a pivotal survival activity of cyclin D1 that protects K-ras oncogene-dependent malignant cells from senescence.
Departamento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo, Brazil.
Fabio L
FL
Forti
Hugo A
HA
Armelin
D000306:Adrenal Cortex Neoplasms / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D011905:Genes, ras; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014667:Vasopressins / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D014667:Vasopressins; D001127:Arginine Vasopressin; D019938:Cyclin D1; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D020169:Caspases; D020742:rhoA GTP-Binding Protein