Activation of GPR54 promotes cell cycle arrest and apoptosis of human tumor cells through a specific transcriptional program not shared by other Gq-coupled receptors.
GPR54 is a receptor for peptides derived from the metastasis suppressor gene KiSS-1. To investigate the intracellular mechanisms involved in the reduction of the metastatic potential of MDA-MB-435S cells expressing GPR54, a time course stimulation by kisspeptin-10 over a period of 25 h was performed using cDNA microarrays. Comparison with the bradykinin B(2) receptor revealed a distinct pattern of gene regulation despite a common coupling to the G(q/11) class of G-proteins. Inhibitors of PLC and PK-C abolished the transcriptional regulation of all tested genes, while an inhibitor of p42/44 affected a subset of genes controlled both by GPR54 and B(2). Among the genes specifically up-regulated by GPR54, we found several proapoptotic genes. Stimulation of GPR54 promoted apoptosis while no significant change was observed after B(2) receptor activation. Our results suggest that the metastasis suppressor properties of GPR54 are mediated in part by cell cycle arrest and induction of apoptosis in malignant cells.
Becker
Jérôme A J
JA
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Campus Erasme, Route de Lennik 808, B-1070 Brussels, Belgium.
Mirjolet
Jean-François
JF
Bernard
Jérôme
J
Burgeon
Emmanuel
E
Simons
Marie-Jeanne
MJ
Vassart
Gilbert
G
Parmentier
Marc
M
Libert
Frédérick
F
D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
C118688:KISS1R protein, human; D043782:Receptor, Bradykinin B2; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide