Cyclin‐dependent kinase 11<sup>p58</sup> interacts with HBO1 and enhances its histone acetyltransferase activity

Zong, Hong; Li, Zejuan; Liu, Liyun; Yun, Hong Shik; Yun, Xiaojing; Jiang, Jianhai; Chi, Yayun; Wang, Hanzhou; Shen, Xıaoyun; Hu, Yun; Niu, Ziyue; Gu, Jianxin

doi:10.1016/j.febslet.2005.05.039

Cited by 21 publications

(10 citation statements)

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“…Several observations support the idea that Hbo1 responds positively to mitogenic signaling pathways to promote replication licensing and proliferation. For example, the cyclin-dependent kinase CDK11 p58 has recently been found to bind Hbo1 and simulate its HAT activity (77). This fits well with our observation that removing the N-terminal serine-rich domain increases Hbo1 HAT activity (Fig.…”

Section: Discussionsupporting

confidence: 81%

Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

Iizuka

Sarmento

Sekiya³

et al. 2008

Molecular and Cellular Biology

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Hbo1 is a histone acetyltransferase (HAT) that is required for global histone H4 acetylation, steroiddependent transcription, and chromatin loading of MCM2-7 during DNA replication licensing. It is the catalytic subunit of protein complexes that include ING and JADE proteins, growth regulatory factors and candidate tumor suppressors. These complexes are thought to act via tumor suppressor p53, but the molecular mechanisms and links between stress signaling and chromatin, are currently unknown. Here, we show that p53 physically interacts with Hbo1 and negatively regulates its HAT activity in vitro and in cells. Two physiological stresses that stabilize p53, hyperosmotic shock and DNA replication fork arrest, also inhibit Hbo1 HAT activity in a p53-dependent manner. Hyperosmotic stress during G 1 phase specifically inhibits the loading of the MCM2-7 complex, providing an example of the chromatin output of this pathway. These results reveal a direct regulatory connection between p53-responsive stress signaling and Hbo1-dependent chromatin pathways.The dynamic regulation of chromatin structure and function is essential for normal cell proliferation and differentiation. This regulation is mediated by several overlapping pathways, including the posttranslational enzymatic modification of histones, the alteration of nucleosome structure by DNA-dependent ATPase complexes, and changes in the histone variant composition of chromatin (4,34,58). Alterations in histone modification enzymes, particularly histone acetyltransferase (HAT) enzymes, have been linked to human cancer (23, 73). Viral oncoproteins, such as adenovirus E1A or simian virus 40 large T antigen, target a number of these enzymes, including p300, CBP, and PCAF. Furthermore, in addition to modifying histones, these HATs can also directly acetylate and activate tumor suppressors and key growth control transcription factors such as p53, Rb, and E2F (24). The MYST family of histone acetyltransferases, named for the four founding proteins in the family (67), can also contribute to carcinogenesis and tumor progression. The MYST proteins are part of large multisubunit HAT complexes conserved from yeast to humans, and they have diverse roles in gene expression, DNA replication, and DNA repair (72). The human MOZ gene, encoding one of the human MYST enzymes, was first identified as a translocation fusion with CBP in acute myeloid leukemias (9). Subsequently, a number of other translocation fusions involving the MYST HATs MOZ and MORF and partners including CBP, p300, MLL, and TIF2 have been identified. It is thought that the mislocalization or misregulation of the HAT activities of these fusions contributes to tumor formation or progression (72).Hbo1 is a member of the MYST family of HAT enzymes and is conserved from flies to humans. It has essential roles in DNA replication and transcription (1,12,22,32,55,59) and is the catalytic subunit of at least two protein complexes comprised of JADE1/JADE2/JADE3 paralogs, hEaf6, and either ING4 or ING5, two members of the "inh...

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Section: Discussionsupporting

confidence: 81%

Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

Iizuka

Sarmento

Sekiya³

et al. 2008

Molecular and Cellular Biology

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“…Hbo1 interacts with Orc1 and Mcm2 (Burke et al, 2001; Iizuka and Stillman, 1999) and is required for DNA replication licensing in mammalian cells and in Xenopus oocyte extracts (Iizuka et al, 2006). Consistent with this role, the enzymatic activity of Hbo1 is activated in telophase by polo-like kinase 1 (Plk1) (Wu and Liu, 2008) and is regulated by cyclin dependent kinases (Zong et al, 2005). Importantly, Hbo1 is specifically detected at DNA replication origins by chromatin immunoprecipitation and may function as a coactivator of the licensing factor Cdt1 (Johmura et al, 2008a; Miotto and Struhl, 2008).…”

Section: Introductionmentioning

confidence: 91%

Histone acetyltransferase Hbo1: Catalytic activity, cellular abundance, and links to primary cancers

Iizuka

Takahashi

Mizzen

et al. 2009

Gene

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In addition to the well-characterized proteins that comprise the pre-replicative complex, recent studies suggest that chromatin structure plays an important role in DNA replication initiation. One of these chromatin factors is the histone acetyltransferase (HAT) Hbo1 which is unique among HAT enzymes in that it serves as a positive regulator of DNA replication. However, several of the basic properties of Hbo1 have not been previously examined, including its intrinsic catalytic activity, its molecular abundance in cells, and its pattern of expression in primary cancer cells. Here we show that recombinant Hbo1 can acetylate nucleosomal histone H4 in vitro, with a preference for lysines 5 and 12. Using semi-quantitative western blot analysis, we find that Hbo1 is approximately equimolar with the number of active replication origins in normal human fibroblasts but is an order of magnitude more abundant in both MCF7 and Saos-2 established cancer cell lines. Immunohistochemistry for Hbo1 in 11 primary human tumor types revealed strong Hbo1 protein expression in carcinomas of the testis, ovary, breast, stomach/esophagus, and bladder.

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“…Prostate-specific antigen (PSA)-LUC and androgen-responsive element (ARE)-LUC reporter plasmids were gifts from Roland Schüle (Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany) (32). HA-CDK11 p58 , pcDNA3-GST-CDK11 p58 , NTD (amino acids 1 to 100), PKD (amino acids 66 to 389), and C-terminal domain (CTD) (amino acids 374 to 439) expression plasmids were constructed as described previously (62). The D224N mutation was generated by site-directed mutagenesis using an MutanBEST kit (Takara) with primers described previously (28).…”

Section: Methodsmentioning

confidence: 99%

“…Cyclin D3 functions not only in G 1 phase as a regulatory subunit of CDK4 and CDK6 but also in G 2 /M phase as a partner of CDK11 p58 during cell cycle progression. The histone acetyltransferase HBO1 was identified as being an interacting protein of CDK11 p58 (62). Both cyclin D3 and HBO1 repress AR transcriptional activity through unknown mechanisms (26,46).…”

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confidence: 99%

Cyclin D3/CDK11^p58 Complex Is Involved in the Repression of Androgen Receptor

Zong

Chi

Wang

et al. 2007

Molecular and Cellular Biology

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Androgen receptor (AR) is essential for the maintenance of the male reproductive systems and is critical for the carcinogenesis of human prostate cancers (PCas). D-type cyclins are closely related to the repression of AR function. It has been well documented that cyclin D1 inhibits AR function through multiple mechanisms, but the mechanism of how cyclin D3 exerts its repressive role in the AR signaling pathway remains to be identified. In the present investigation, we demonstrate that cyclin D3 and the 58-kDa isoform of cyclin-dependent kinase 11 (CDK11 p58 ) repressed AR transcriptional activity as measured by reporter assays of transformed cells and prostate-specific antigen expression in PCa cells. AR, cyclin D3, and CDK11 p58 formed a ternary complex in cells and were colocalized in the luminal epithelial layer of the prostate. AR activity is controlled by phosphorylation at specific sites. We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11 p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). Furthermore, androgen-dependent proliferation of PCa cells was inhibited by cyclin D3/CDK11 p58 through AR repression. These data suggest that cyclin D3/CDK11 p58 signaling is involved in the negative regulation of AR function.Androgen receptor (AR), a member of the nuclear receptor family, directly regulates patterns of gene expression in response to the steroids testosterone and dihydrotestosterone (DHT) and is subsequently involved in the regulation of the development and differentiation of the male reproductive system (10). Similar to other steroid receptors, AR contains a transactivation domain (TAD), also named AF-1, in its N terminus, a ligand binding domain (LBD) in its C terminus, a DNA-binding domain (DBD), and a hinge region between the TAD and LBD. The transcriptional activation unit 1 (TAU1) and TAU5 motifs in the AR N-terminal domain (NTD) (residues 101 to 370 and 360 to 485, respectively) as well as the AF-2 motif in the AR LBD have been implicated in directly contacting p160 proteins and mediating transcription (1,23,31,48).AR is a phosphoprotein whose function is regulated by the modulation of its phosphorylation status at different sites (4). The consensus phosphorylation sites found in AR indicate that AR could be a substrate for DNA-dependent kinase, protein kinase A, protein kinase C, mitogen-activated protein kinase, and casein kinase 2 (4). Ser-16, Ser-81, Ser-94, Ser-256, Ser-308, Ser-424, and Ser-650 have been identified as being phosphorylation sites of AR by mutagenesis, peptide mapping, and mass spectrometry (6, 60). Recently, several Ser/Thr protein kinases have been found to phosphorylate AR at the abovementioned sites in vitro and in vivo. For example, AR Ser-515 is phosphorylated by mitogen-activated protein kinase, Ser-213 and Ser-791 are phosphorylated by Akt, and Ser-650 is phosphorylated by p38␣ and JNK1 (17,30,57).More and more studies suggest that cyclins and cyclin-dependent kinases (CDKs) are also involved in th...

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Cyclin‐dependent kinase 11^p58 interacts with HBO1 and enhances its histone acetyltransferase activity

Cited by 21 publications

References 45 publications

Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

Histone acetyltransferase Hbo1: Catalytic activity, cellular abundance, and links to primary cancers

Cyclin D3/CDK11^p58 Complex Is Involved in the Repression of Androgen Receptor

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Cyclin‐dependent kinase 11p58 interacts with HBO1 and enhances its histone acetyltransferase activity

Cited by 21 publications

References 45 publications

Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

Histone acetyltransferase Hbo1: Catalytic activity, cellular abundance, and links to primary cancers

Cyclin D3/CDK11p58 Complex Is Involved in the Repression of Androgen Receptor

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Cyclin‐dependent kinase 11^p58 interacts with HBO1 and enhances its histone acetyltransferase activity

Cyclin D3/CDK11^p58 Complex Is Involved in the Repression of Androgen Receptor