title: GFAP-Cre-mediated transgenic activation of Bmi1 results in pituitary tumors.
abstract: Bmi1 is a member of the polycomb repressive complex 1 and plays different roles during embryonic development, depending on the developmental context. Bmi1 over expression is observed in many types of cancer, including tumors of astroglial and neural origin. Although genetic depletion of Bmi1 has been described to result in tumor inhibitory effects partly through INK4A/Arf mediated senescence and apoptosis and also through INK4A/Arf independent effects, it has not been proven that Bmi1 can be causally involved in the formation of these tumors. To see whether this is the case, we developed two conditional Bmi1 transgenic models that were crossed with GFAP-Cre mice to activate transgenic expression in neural and glial lineages. We show here that these mice generate intermediate and anterior lobe pituitary tumors that are positive for ACTH and beta-endorphin. Combined transgenic expression of Bmi1 together with conditional loss of Rb resulted in pituitary tumors but was insufficient to induce medulloblastoma therefore indicating that the oncogenic function of Bmi1 depends on regulation of p16(INK4A)/Rb rather than on regulation of p19(ARF)/p53. Human pituitary adenomas show Bmi1 overexpression in over 50% of the cases, which indicates that Bmi1 could be causally involved in formation of these tumors similarly as in our mouse model.
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Bart A
authors.initials: BA
authors.lastname: Westerman
authors.forename: Marleen
authors.initials: M
authors.lastname: Blom
authors.forename: Ellen
authors.initials: E
authors.lastname: Tanger
authors.forename: Martin
authors.initials: M
authors.lastname: van der Valk
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Marije
authors.initials: M
authors.lastname: van Santen
authors.forename: Jules
authors.initials: J
authors.lastname: Gadiot
authors.forename: Paulien
authors.initials: P
authors.lastname: Cornelissen-Steijger
authors.forename: John
authors.initials: J
authors.lastname: Zevenhoven
authors.forename: Haydn M
authors.initials: HM
authors.lastname: Prosser
authors.forename: Anthony
authors.initials: A
authors.lastname: Uren
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D006801:Humans; D019426:Integrases / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000473:pathology; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism; D019076:Transgenes / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005904:Glial Fibrillary Acidic Protein; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D001615:beta-Endorphin; D063150:Polycomb Repressive Complex 1; C045073:Cre recombinase; D019426:Integrases