Androgen receptor interacts with a novel MYST protein, HBO1
ABSTRACT The androgen receptor (AR), a member of the nuclear receptor superfamily, plays a central role in male sexual differentiation and prostate cell proliferation. Results of treating prostate cancer by androgen ablation indicate that signals mediated through AR are critical for the growth of these tumors. Like other nuclear receptors, AR exerts its transcriptional function by binding to cis-elements upstream of promoters and interacting with other transcriptional factors (e.g. activators, repressors and modulators). To determine the mechanism of AR-regulated transcription, we used the yeast two-hybrid system to identify AR-associated proteins. One of the proteins we identified is identical to the human origin recognition complex-interacting protein termed HBO1. A ligand-enhanced interaction between AR and HBO1 was further confirmed in vivo and in vitro. Immunofluorescence experiments showed that HBO1 is a nuclear protein, and Northern blot analysis revealed that it is ubiquitously expressed, with the highest levels present in human testis. HBO1 belongs to the MYST family, which is characterized by a highly conserved C2HC zinc finger and a putative histone acetyltransferase domain. Surprisingly, two yeast members of the MYST family, SAS2 and SAS3, have been shown to function as transcription silencers, despite the presence of the histone acetyltransferase domain. Using a GAL4 DNA-binding domain assay, we mapped a transcriptional repression domain within the N-terminal region of HBO1. Transient transfection experiments revealed that HBO1 specifically repressed AR-mediated transcription in both CV-1 and PC-3 cells. These results indicate that HBO1 is a new AR-interacting protein capable of modulating AR activity. It could play a significant role in regulating AR-dependent genes in normal and prostate cancer cells.
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ABSTRACT: CDK11(p58), a 58kDa protein of the PITSLRE kinase family, plays an important role in cell cycle progression, and is closely related to cell apoptosis. To gain further insight into the function of CDK11(p58), we screened a human fetal liver cDNA library for its interacting proteins using the yeast two-hybrid system. Here we report that histone acetyltransferase (HAT) HBO1, a MYST family protein, interacts with CDK11(p58) in vitro and in vivo. CDK11(p58) and HBO1 colocalize in the cell nucleus. Recombinant CDK11(p58) enhances the HAT activity of HBO1 significantly in vitro. Meanwhile, overexpression of CDK11(p58) in mammalian cells leads to the enhanced HAT activity of HBO1 towards free histones. Thus, we conclude that CDK11(p58) is a new interacting protein and a novel regulator of HBO1. Both of the proteins may be involved in the regulation of eukaryotic transcription.FEBS Letters 08/2005; 579(17):3579-88. DOI:10.1016/j.febslet.2005.05.039 · 3.34 Impact Factor
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ABSTRACT: Screening of an embryonic chick cDNA library revealed a gene product termed chick TIP60 (cTIP60) due to its homology with human TIP60, a founding member of the "MYST" family of proteins that possess functional motifs, including chromo, zinc finger, and histone acetyltransferase domains. cTIP60 expression was assessed during early chick embryogenesis, at the RNA level by using reverse transcriptase-polymerase chain reaction (RT-PCR) and at the protein level by using Western blotting and immunohistochemistry. RT-PCR indicated that cTIP60 transcripts in whole embryos are present as early as Hamburger-Hamilton (HH) stage 5, diminishing after HH10. Western blotting of total embryonic protein revealed that cTIP60 was present in uniform quantities between HH3 and HH25. By contrast, Western blotting of protein from isolated hearts revealed that cTIP60 protein was strongly expressed at the earliest stages of heart development (HH11-13), diminishing thereafter. This finding was corroborated by immunohistochemistry, which revealed that cTIP60 protein was selectively expressed at high levels in the myocardium between HH 10-14. Considered in the context of its functional domains, these findings suggest that cTIP60 modulates transcriptional processes which regulate terminal cell differentiation, proliferation, or both, during early myocardial development.Developmental Dynamics 03/2002; 223(3):419-25. DOI:10.1002/dvdy.10058 · 2.67 Impact Factor
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ABSTRACT: It is well established that acetylation of histone and nonhistone proteins is intimately linked to transcriptional activation. However, loss of acetyltransferase activity has also been shown to cause silencing defects, implicating acetylation in gene silencing. The something about silencing (Sas) 2 protein of Saccharomyces cerevisiae, a member of the MYST (MOZ, Ybf2/Sas3, Sas2, and TIP60) acetyltransferase family, promotes silencing at HML and telomeres. Here we identify a ~450-kD SAS complex containing Sas2p, Sas4p, and the tf2f-related Sas5 protein. Mutations in the conserved acetyl-CoA binding motif of Sas2p are shown to disrupt the ability of Sas2p to mediate the silencing at HML and telomeres, providing evidence for an important role for the acetyltransferase activity of the SAS complex in silencing. Furthermore, the SAS complex is found to interact with chromatin assembly factor Asf1p, and asf1 mutants show silencing defects similar to mutants in the SAS complex. Thus, ASF1-dependent chromatin assembly may mediate the role of the SAS complex in silencing.Genes & Development 01/2002; 15(23):3155-68. DOI:10.1101/gad.907201 · 12.64 Impact Factor