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.
Highlights
Several recent studies have identified functional interactions between cyclin D1 and diverse transcription factors
Mutational analysis demonstrated that the regulation of transcription factor activity by cyclin D1 was independent of the residues required for binding cyclin-dependent kinase (Cdk) [10, 11]
The domains conserved between p300 and CBP include a histone acetyltransferase (HAT) domain, a bromo domain, three cysteine- and histidine-rich domains (CH), and a cell cycle regulatory domain (CRD1). p300 was initially cloned as an E1A interacting protein (14 –16), and the formation of the multimeric complex between p300 and E1A is important in overcoming normal growth control, as E1A mutants that fail to bind p300 cannot efficiently transform cells [17]. p300 forms a physical bridge between transcription factors and the basal transcription apparatus to coordinate regulation of gene transcription
Summary
Cyclin-dependent kinase; CBP, cAMP-response element-binding protein-binding protein; LPL, lipoprotory subunit cyclin binds and activates their catalytic partners, or Cdks, allowing phosphorylation of a series of critical cellular substrates, thereby promoting cell cycle progression [1]. Cyclin D1-deficient animals show enhanced adipocyte differentiation in response to PPAR␥ ligands As this phenotype was reversed tein lipase; PPAR, peroxisome proliferator-activated receptor; PPARE, PPAR␥-responsive element; IRES, internal ribosome entry site; GFP, green fluorescent protein; HAT, histone acetyltransferase; MEF, mouse embryonic fibroblast; TSA, trichostatin A; ChIP, chromatin immunoprecipitation; HDAC, histone deacetylase; CH, cysteine- and histidinerich domains; CMV, cytomegalovirus; pRb, retinoblastoma protein; MSCV, murine stem cell virus. P21CIP1/WAF1 augments HAT activity of p300/ CBP and de-represses p300 through the CRD1 domain It induces p300-dependent transcription in a promoter-specific manner [23, 24]. Our results suggest that cyclin D1 plays an important role to modulate p300 activity and its target gene expression
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