Acetylation of nuclear receptors in cellular growth and apoptosis

doi:10.1016/j.bcp.2004.05.037

Biochemical Pharmacology

Volume 68, Issue 6, 15 September 2004, Pages 1199-1208

https://doi.org/10.1016/j.bcp.2004.05.037 Get rights and content

Abstract

Post-translational modification of chromatin histones governs a key mechanism of transcriptional regulation. Histone acetylation, together with methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, and ADP ribosylation, modulate the activity of many genes by modifying both core histones and non-histone transcription factors. Epigenetic protein modification plays an important role in multiple cellular processes including DNA repair, protein stability, nuclear translocation, protein–protein interactions, and in regulation of cellular proliferation, differentiation and apoptosis.

Histone acetyltransferases modify histones, coactivators, nuclear transport proteins, structural proteins, cell cycle components and transcription factors including p53 and nuclear receptors. The estrogen, PPARγ and androgen receptor are members of the nuclear receptor (NR) superfamily. The androgen receptor (AR) and estrogen receptor α (ERα) are directly acetylated by histone acetyltransferases at a motif that is conserved between species and other NR. Point mutations at the lysine residue within the acetylation motif of the AR and ERα have been identified in prostate cancer as well as in breast cancer tissue. Acetylation of the NR governs ligand sensitivity and hormone antagonist responses. The AR is acetylated by p300, P/CAF and TIP60 and acetylation of the AR regulates co-regulator recruitment and growth properties of the receptors in cultured cells and in vivo. AR acetylation mimic mutants convey reduced apoptosis and enhanced growth properties correlating with altered promoter specificity for cell-cycle target genes. Cell-cycle control proteins, including cyclins, in turn alter the access of transcription factors and nuclear receptors to the promoters of target genes.

Introduction

Activation of target genes by hormones requires chromatin remodeling and histone modifications. Whereas DNA sequences within chromatin serve as genetic code for gene expression, post-translational modifications of core histones comprise an epigenetic “histone code” that modulates the local chromatin structure and determines the accessibility of transcriptional co-regulators to the underlying DNA. A diverse array of covalent modifications of the amino acid residues in the histone tails including acetylation, phosphorylation, methylation and ubiquitylation have been reported. Distinct histone modifications, which act sequentially or in combination, dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states [1], [2], [3], [4], [5]. Post-translational modification of histone proteins as well as non-histone proteins including nuclear receptors integrates signaling pathways mediating diverse biological processes. This review will focus on the biological significance of nuclear receptors modification by acetylation.

Section snippets

Histone acetyltransferases and deacetylases

In eukaryotes, DNA is packaged by histones into nucleosomes which are composed of 147 base pairs of DNA and core histone proteins H2A, H2B, H3 and H4. Alterations in the localize chromatin structure has an important impact on genetic transcriptional responses. Chromatin remodeling complexes and enzymes involved in post-translational modifications of the histone components of chromatin play important roles in transcriptional regulation.

The histone acetyltransferases (HAT) and histone

Acetylation of non-histone targets

Accumulating evidences suggest that substrates of HATs and HDACs are not limited to histones. A subset of transcription factors such as p53 [11], [12], GATA-1 [13], GATA-2 [14], GATA-3 [15], EKLF [16], HMG box architectural factor UBF [Pelletier, 2000, no. 245], AML1 [17], and hormone nuclear receptors, such as AR [18], [19], [20], [21], ER α [22] are regulated by acetylation. Through modification of histone and nonhistone substrates, histone acetyltransferase complexes are involved in diverse

Nuclear receptor superfamily

The NR superfamily encodes structurally related proteins including receptors for steroid and thyroid hormones, retinoic acid, vitamins, and other proteins for which no ligands have been found (orphan receptors) [23]. Nuclear hormone receptors function as ligand-activated transcription factors. The functional domains of the NR are conserved within the superfamily members and include the activation function region (AF), DNA binding domain (DBD), hinge region and ligand-binding domain (LBD). The

Nuclear receptor co-regulators

Co-regulators (coactivators and corepressors) convey both intrinsic enzymatic activities and recruit enzymes to molecular interactions to modulate gene expression in response to hormonal signals [29]. Coactivators associate with NR in a ligand-dependent manner and are essential for ligand-induced NR activation (see Fig. 1). A large number of coactivators/adaptors of NR family have been identified during recent years, including steroid receptor coactivator-1 (SRC-1), amplified in breast cancer

Acetylation modification of nuclear receptors

Regulation of nuclear receptor gene expression involves dynamic and coordinated interactions with HATs and HDAC complexes, which are components of the NR coactivator or corepressor complexes. Nuclear receptor members, such as the AR and ERα, are direct substrates of histone acetyltransferase in vitro and in vivo [18], [19], [20], [21], [22]. The candidate acetylation motif KXKK/RXKK of the nuclear receptor members such as TR, RAR, PPAR, LXR, FXR, VDR, GR, PR, HNF4, and SF1 are phylogenetically

Sumoylation of the nuclear receptors

Sumoylation is an enzymatic process involving the attachment of a small protein moiety, SUMO, to substrate proteins. Although biochemically analogous to ubiquitylation, conjugation of SUMO does not typically lead to degradation of the substrate [83], [84]. A subset of cellular proteins, including histone H4, MEK1, CCAAT/enhancer-binding proteins (CEBP), topoisomerase I, Tcf-4, Smad4, p53, MDM2, pancreatic duodenal homeobox-1 (Pdx1), the transcription corepressor CtBP are sumoylated [83], [85],

Conclusions

Post-translational medications of the NRs and interaction of NR with coactivators and corepressors play important roles in modulating NR functions. A subset of evolutionarily related NR family members contain a potential acetylation motif implicating acetylation is involved in regulating multiple distinct hormone signals. The NR coactivators SRC1, AIB1, and p300 are overexpressed in human cancer and residues within the acetylated motif of NR are mutated in cancer. Lysine acetylation mimic

Acknowledgements

We apologize to the investigators whose work has not been cited due to space limitations. This work was supported in part by awards from the Susan Komen Breast Cancer Foundation, Breast Cancer Alliance Inc., and research grants R01CA70896, R01CA75503, R01CA86072, R01CA86071 from NIH (to R.G.P.) and R21DK065220-02 from NIDDK (to M.F.).

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Acetylation of nuclear receptors in cellular growth and apoptosis

Abstract

Introduction

Section snippets

Histone acetyltransferases and deacetylases

Acetylation of non-histone targets

Nuclear receptor superfamily

Nuclear receptor co-regulators

Acetylation modification of nuclear receptors

Sumoylation of the nuclear receptors

Conclusions

Acknowledgements

Curr. Opin. Genet. Dev.

Mol. Cell

Trends Genet.

Semin. Cell Dev. Biol.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Curr. Opin. Biotechnol.

Curr. Opin. Genet. Dev.

Vitam Horm

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

Cytokine Growth Factor Rev.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

Urology

Urology

Cell

Cell

Cell

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

Exp. Cell Res.

Virus Res.

Mol Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Dev. Cell

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J. Biol. Chem.

J. Biol. Chem.

Proc. Natl. Acad. Sci. U.S.A.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

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Nature

Translating the histone code

Science

Identification of methylation and acetylation sites on mouse histone H3 using matrix-assisted laser desorption/ionization time-of-flight and nanoelectrospray ionization tandem mass spectrometry

J. Protein Chem.

Histone deacetylases (HDACs): characterization of the classical HDAC family

Biochem. J.

Histone deacetylases: unique players in shaping the epigenetic histone code

Ann. NY Acad. Sci.

Acetylation and phosphorylation of the carboxy-terminal domain of p53: regulative significance

Oncol. Res.