title: Cyclin D1 represses p300 transactivation through a cyclin-dependent kinase-independent mechanism.
abstract: Cyclin D1 encodes a regulatory subunit, which with its cyclin-dependent kinase (Cdk)-binding partner forms a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. In addition to its Cdk binding-dependent functions, cyclin D1 regulates cellular differentiation in part by modifying several transcription factors and nuclear receptors. The molecular mechanism through which cyclin D1 regulates the function of transcription factors involved in cellular differentiation remains to be clarified. The histone acetyltransferase protein p300 is a co-integrator required for regulation of multiple transcription factors. Here we show that cyclin D1 physically interacts with p300 and represses p300 transactivation. We demonstrated further that the interaction of the two proteins occurs at the peroxisome proliferator-activated receptor gamma-responsive element of the lipoprotein lipase promoter in the context of the local chromatin structure. We have mapped the domains in p300 and cyclin D1 involved in this interaction. The bromo domain and cysteine- and histidine-rich domains of p300 were required for repression by cyclin D1. Cyclin D1 repression of p300 was independent of the Cdk- and retinoblastoma protein-binding domains of cyclin D1. Cyclin D1 inhibits histone acetyltransferase activity of p300 in vitro. Microarray analysis identified a signature of genes repressed by cyclin D1 and induced by p300 that promotes cellular differentiation and induces cell cycle arrest. Together, our results suggest that cyclin D1 plays an important role in cellular proliferation and differentiation through regulation of p300.
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Maofu
authors.initials: M
authors.lastname: Fu
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wu
authors.forename: Toula
authors.initials: T
authors.lastname: Bouras
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.forename: Jianguo
authors.initials: J
authors.lastname: Yang
authors.forename: Anping
authors.initials: A
authors.lastname: Li
authors.forename: Neil D
authors.initials: ND
authors.lastname: Perkins
authors.forename: Bayar
authors.initials: B
authors.lastname: Thimmapaya
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Alberto
authors.initials: A
authors.lastname: Munoz
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D019938:Cyclin D1 / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology; D011506:Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D011506:Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases; D006655:Histone Deacetylases