Cooperation between cyclin E and p27(Kip1) in pituitary tumorigenesis.
Cushing's disease is caused by glucocorticoid-resistant pituitary corticotroph adenomas. We have previously identified the loss of nuclear Brg1 as one mechanism that may lead to partial glucocorticoid resistance: this loss is observed in about 33% of human corticotroph adenomas. We now show that Brg1 loss of function correlates with cyclin E expression in corticotroph adenomas and with loss of the cell cycle inhibitor p27(Kip1) expression. Because Brg1 is thought to have tumor suppressor activity, the present study was undertaken to understand the putative contribution of cyclin E derepression produced by loss of Brg1 expression on adenoma development. Overexpression of cyclin E in pituitary proopiomelanocortin cells leads to abnormal reentry into cell cycle of differentiated proopiomelanocortin cells and to centrosome instability. These alterations are consistent with the intermediate lobe hyperplasia and anterior lobe adenomas that were observed in these pituitaries. When combined with the p27(Kip1) knockout, overexpression of cyclin E increased the incidence of pituitary tumors, their size, and their proliferation index. These results suggest that cyclin E up-regulation and p27(Kip1) loss-of-function act cooperatively on pituitary adenoma development.
Roussel-Gervais
Audrey
A
Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, Quebec, Canada H2W 1R7.
Bilodeau
Steve
S
Vallette
Sophie
S
Berthelet
France
F
Lacroix
André
A
Figarella-Branger
Dominique
D
Brue
Thierry
T
Drouin
Jacques
J
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006965:Hyperplasia; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D047748:Pituitary ACTH Hypersecretion / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism
D015415:Biomarkers; D019927:Cyclin E; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011333:Pro-Opiomelanocortin; C513194:Smarca4 protein, mouse; D004265:DNA Helicases