title: The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease.
abstract: BACKGROUND
  Cushing disease (CD) is due to pituitary corticotrope adenomas that produce unrestrained ACTH secretion and have lost the negative feedback exerted by glucocorticoids (GCs). GCs also restrain corticotrope proliferation, and the mechanisms of this inhibition are poorly understood.
  
  
  OBJECTIVE
  The aim of the study was to identify cell cycle regulatory genes that are regulated by GCs and the glucocorticoid receptor and to assess regulatory genes that have a rate-limiting action on corticotrope proliferation and may be disregulated in CD.
  
  
  METHODS
  The mouse corticotrope tumor cells AtT-20 were used to identify GC-regulated genes that contribute to control of cell cycle progression. Surgery sections from patients with CD were used to assess expression of CABLES1 in corticotrope adenomas.
  
  
  METHODS
  Gene expression profiling, small interfering RNA knockdowns, cell cycle analyses, and genetic manipulations were performed in AtT-20 cells. Sequencing of chromatin immunoprecipitation for pituitary-restricted transcription factors and RNA polymerase II were used to identify regulatory elements and genes that bind GR and are direct transcriptional targets. A panel of previously well-characterized corticotrope adenomas was used to correlate expression of CABLES1 with that of other markers.
  
  
  RESULTS
  GCs altered expression of 3 positive and 3 negative regulators of cell cycle progression. Two Myc genes (L-Myc and N-Myc) and E2F2 are repressed by GCs, whereas genes for the negative regulators of the cell cycle, Gadd45β, Gadd45γ, and Cables1 are activated by GCs. Cables1 small interfering RNA knockdown strongly stimulates AtT-20 cell proliferation and antagonizes the growth inhibition produced by GCs. The Gadd45 and Cables1 genes have the hallmarks of direct GC targets. CABLES1 is expressed in normal human pituitary cells, but expression is lost in ∼55% of corticotrope adenomas, and this is strongly correlated with the loss of p27(Kip1) expression.
  
  
  CONCLUSIONS
  CABLES1 is a critical regulator of corticotrope proliferation that defines a pathway often inactivated in CD and links proliferation to GC resistance.
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Roussel-Gervais
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Couture
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Takayasu
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Balsalobre
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Zukerberg
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Brue
authors.affiliation: Laboratoire de Génétique Moléculaire (A.R.-G., C.C., D.L., S.T., A.B., J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada; Massachusetts General Hospital (B.R.R., L.R.Z., J.D.), Boston, Massachusetts 02114; Aix-Marseille Université (D.F.-B., T.B.), Centre National de la Recherche Scientifique, Center for Research in Neurobiology and Neurophysiology of Marseille, Unité Mixte de Recherche 7286, 13344 Marseille, France; and Assistance Publique-Hôpitaux de Marseille (D.F.-B., T.B.), Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, 13285 Marseille, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Drouin
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016213:Cyclins / Q000235:genetics*; D050703:E2F2 Transcription Factor / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D018816:Genes, cdc / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010902:Pituitary Gland / Q000473:pathology*; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid / Q000235:genetics
chemical_list: C486568:CABLES1 protein, human; C411580:Cables1 protein, mouse; D002352:Carrier Proteins; D016213:Cyclins; D050703:E2F2 Transcription Factor; C484940:E2f2 protein, mouse; D005938:Glucocorticoids; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D000324:Adrenocorticotropic Hormone