Trithorax requires Hsp90 for maintenance of active chromatin at sites of gene expression

Tariq, Muhammad; Nussbaumer, Ute; Chen, Yujie; Beisel, Christian; Paro, Renato

doi:10.1073/pnas.0809669106

Cited by 115 publications

(143 citation statements)

References 48 publications

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“…It has been shown in many earlier studies that heat shock proteins and other chaperones are associated with nuclear matrix (37,38). It has also been shown in a recent study that molecular chaperone Hsp90 interacts with Trithorax to maintain active chromatin at sites of gene expression (39). In addition to a number of heat shock proteins such as Hsp26, -27, -83, and -70A, we identified few novel molecular chaperones that have ATPase activity and unfolded protein binding activity as a part of the nuclear matrix.…”

Section: Discussionmentioning

confidence: 96%

Nuclear Matrix Proteome Analysis of Drosophila melanogaster

Kallappagoudar

Varma

Pathak

et al. 2010

Molecular & Cellular Proteomics

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The nucleus is a highly structured organelle and contains many functional compartments. Although the structural basis for this complex spatial organization of compartments is unknown, a major component of this organization is likely to be the non-chromatin scaffolding called nuclear matrix (NuMat). Experimental evidence over the past decades indicates that most of the nuclear functions are at least transiently associated with the NuMat, although the components of NuMat itself are poorly known. Here, we report NuMat proteome analysis from Drosophila melanogaster embryos and discuss its links with nuclear architecture and functions. In the NuMat proteome, we found structural proteins, chaperones, DNA/RNAbinding proteins, chromatin remodeling and transcription factors. This complexity of NuMat proteome is an indicator of its structural and functional significance. The eukaryotic cell nucleus contains a number of structural features like heterochromatin, nucleolus, nuclear lamina, and nuclear territories and functional features like transcription foci, replication foci, Cajal bodies, stress-induced foci, etc.(1-7). Packaging of the genome on the other hand also results in non-random distribution of a variety of structural features like chromatin domains that help to regulate expression of genes (8). How these complex structural and functional domains are established and maintained is not known. It is likely that the non-chromatin scaffolding called nuclear matrix (9) plays an important role in this process. Nuclear matrix (NuMat) 1 mainly consists of the nuclear lamina, the nucleolar remnants, and an internal nuclear meshwork of fibers of unknown constitution that can be seen by electron microscopy (10). These fibers have ultrastructural features reminiscent of intermediate filaments of the cytosol (11). The protein component of nucleoplasmic filaments, however, is largely unknown. Earlier studies on a few proteins isolated from nuclear matrix from different organisms have shown them to be DNA-and RNA-binding and structural components of the nuclear pore complex (12), enzymes (13), and nuclear membrane proteins (14). This diversity among the small number of identified NuMat constituents reflects the link of nuclear architecture with the variety of nuclear functions. The importance of NuMat constituents in nuclear processes has been apparent for a long time, and several studies have been carried out to identify the proteins of this complex structure in different organisms (15-18). Major advancements in the field of proteomics now provide further scope for extensive analysis of NuMat in this context.Here, we present a comprehensive analysis of the NuMat proteome of Drosophila melanogaster. NuMat preparations from D. melanogaster embryos were separated by one-dimensional gel electrophoresis, and the proteins were identified by LC-MS/MS. We also report a remarkable variation in the NuMat proteome depending on developmental stages, indicating a link between embryonic development and nuclear architecture. Finally, immunos...

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Section: Discussionmentioning

confidence: 96%

Nuclear Matrix Proteome Analysis of Drosophila melanogaster

Kallappagoudar

Varma

Pathak

et al. 2010

Molecular & Cellular Proteomics

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“…TRAP1 is localized in mitochondria, where it functions as a protective factor against oxidative stress (15,16). HSP90 proteins are involved in cellular homeostasis (17), transcriptional regulation (18), and chromatin remodeling (19). Because HSP90 is a molecular chaperone of numerous oncoproteins, it is considered to be a crucial facilitator of oncogene addiction (a unique characteristic of cancer cells that makes them dependent on one or more oncogenic proteins for their survival) (2) and is a validated anticancer drug target (2).…”

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confidence: 99%

Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

Solier

Kohn²,

Scroggins³

et al. 2012

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

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The “apoptotic ring” is characterized by the phosphorylation of histone H2AX at serine 139 (γ-H2AX) by DNA-dependent protein kinase (DNA-PK). The γ-H2AX apoptotic ring differs from the nuclear foci patterns observed in response to DNA-damaging agents. It contains phosphorylated DNA damage response proteins including activated Chk2, activated ATM, and activated DNA-PK itself but lacks MDC1 and 53BP1, which are required to initiate DNA repair. Because DNA-PK can phosphorylate heat shock protein 90α (HSP90α) in biochemical assays, we investigated whether HSP90α is involved in the apoptotic ring. Here we show that HSP90α is phosphorylated by DNA-PK on threonines 5 and 7 early during apoptosis and that both phosphorylated HSP90α and DNA-PK colocalize in the apoptotic ring. We also show that DNA-PK is a client of HSP90α and that HSP90α is required for full DNA-PK activation, γ-H2AX formation, DNA fragmentation, and apoptotic body formation. In contrast, HSP90 inhibition by geldanamycin markedly enhances TRAIL-induced DNA-PK and H2AX activation. Together, our results reveal that HSP90α is a substrate and chaperone of DNA-PK in the apoptotic response. The response of phosphorylated HSP90α to TRAIL and its localization to the γ-H2AX ring represent epigenetic features of apoptosis that offer insights for studying and monitoring nuclear apoptosis.

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“…Recent studies have implicated HSP90 in transcriptional regulation demonstrating an important role for it in buffering genetic and epigenetic variation leading to altered phenol-types. It cooperates with Trithorax (a TrxG chromatin protein) maintaining the active expression state of targets like the Hox genes [133]. Aberrant expression of Hox genes is related to the development of breast cancer and the malignant behaviour of cancer cells, and the expression of HoxC5 is lower in cancerous tissues with mutated-type p53 than in normal and cancerous tissues with wild-type p53 [134,135].…”

Section: Predictive and Therapeutic Implications Of Hsp Expression Inmentioning

confidence: 99%

The Role of Heat Shock Proteins in Mammary Neoplasms: A Brief Review

Salda¹,

Romanucci²

2012

JCT

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Research into heat shock proteins (HSPs) for the clinical management of tumours has intensified as new evidence shows they can be used as biomarkers in carcinogenesis and are related to poor prognosis in some cancer types. Members of small HSP, HSP70 and HSP90 families have been studied extensively in breast cancer. This article reviews current understanding of the role of HSP and HSF-1 (Heat shock factor 1) expression in human breast cancer and looks at its potential diagnostic, prognostic and therapeutic value. The exciting progress that has been made using HSP 90 inhibitors in breast cancer treatment is examined and the results of preliminary studies on the expression of stress proteins in the animal model canine mammary tumours are also presented.

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Trithorax requires Hsp90 for maintenance of active chromatin at sites of gene expression

Cited by 115 publications

References 48 publications

Nuclear Matrix Proteome Analysis of Drosophila melanogaster

Nuclear Matrix Proteome Analysis of Drosophila melanogaster

Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

The Role of Heat Shock Proteins in Mammary Neoplasms: A Brief Review

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