title: Cyclin D1 and C/EBPβ LAP1 operate in a common pathway to promote mammary epithelial cell differentiation.
abstract: Both cyclin D1 and the transcription factor C/EBPβ are required for mammary epithelial cell differentiation; however, the pathway in which they operate is uncertain. Previous analyses of the patterns of gene expression in human tumors suggested a connection between cyclin D1 overexpression and C/EBPβ, but whether this represents a cancer-specific gain of function for cyclin D1 is unknown. C/EBPβ is an intronless gene encoding three protein isoforms--LAP1, LAP2, and LIP. Here, we provide evidence that cyclin D1 engages C/EBPβ in an isoform-specific manner. Cyclin D1 binds to LAP1, an event that activates the transcriptional function of LAP1 by relieving its autoinhibited state effected by intramolecular interactions. Reexpression of LAP1 but not LAP2 or LIP restores the ability of C/EBPβ-deficient mammary epithelial cells to differentiate and does so in a manner dependent on cyclin D1. And cyclin D1-mediated activation of LAP1 participates in mammary epithelial cell differentiation. Our findings indicate that cyclin D1 and C/EBPβ LAP1 operate in a common pathway to promote mammary epithelial cell differentiation.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Boudot
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hennessey
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Beauparlant
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Hasan N
authors.initials: HN
authors.lastname: Rajabi
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Zahnow
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA Dana-Farber Cancer Institute, Boston, Massachusetts, USA mewen@tuftsmedicalcenter.org.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Ewen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C530104:CCND1 protein, human; C545012:CEBPB protein, human; D020033:Protein Isoforms; D019938:Cyclin D1