Heat Shock Protein 90 (Hsp90) Selectively Regulates the Stability of KDM4B/JMJD2B Histone Demethylase

Ipenberg, Inbal; Guttmann‐Raviv, Noga; Khoury, Hanan P.; Kupershmit, Ilana; Ayoub, Nabieh

doi:10.1074/jbc.c113.462770

Cited by 30 publications

(23 citation statements)

References 36 publications

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“…Future studies will indicate whether the regulatory component mediated by GPS2 also represents a conserved mechanism contributing to the regulation of other nuclear receptors’ activity, including LXR, ER and AR. Importantly, regulatory mechanisms based on stabilization of histone demethylases may represent unexplored druggable targets in the treatment of human diseases as indicated by the recent finding of KDM4B stabilization by Hsp90 in tumors (Ipenberg et al 2013). …”

Section: Discussionmentioning

confidence: 99%

GPS2/KDM4A Pioneering Activity Regulates Promoter-Specific Recruitment of PPARγ

et al. 2014

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Timely and selective recruitment of transcription factors to their appropriate DNA-binding sites represents a critical step in regulating gene activation; however the regulatory strategies underlying each factor’s effective recruitment to specific promoter and/or enhancer regions are not fully understood. Here, we identify an unexpected regulatory mechanism by which promoter-specific binding, and therefore function, of PPARγ in adipocytes requires G protein Suppressor 2 (GPS2) to prime the local chromatin environment via inhibition of the ubiquitin ligase RNF8 and stabilization of the H3K9 histone demethylase KDM4A/JMJD2. Integration of genome-wide profiling data indicates that the pioneering activity of GPS2/KDM4A is required for PPARγ–mediated regulation of a specific transcriptional program, including the lipolytic enzymes ATGL and HSL. Hence, our findings reveal that GPS2 exerts a biologically important function in adipose tissue lipid mobilization by directly regulating ubiquitin signaling and indirectly modulating chromatin remodeling to prime selected genes for activation.

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Section: Discussionmentioning

confidence: 99%

GPS2/KDM4A Pioneering Activity Regulates Promoter-Specific Recruitment of PPARγ

et al. 2014

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“…Heat shock protein 90 is necessary for the dephosphorylating state of BES1 protein ATPase activity of HSP90 is crucially important for binding to its client proteins (Ipenberg et al, 2013). A client of HSP90, BES1 is reportedly regulated in the phosphorylation status by BR levels (Yin et al, 2002).…”

Section: Heat Shock Protein 903 Interacts With the Amino Terminal Anmentioning

confidence: 99%

Heat shock protein 90 acts in brassinosteroid signaling through interaction with BES1/BZR1 transcription factor

Shigeta

Zaizen

Sugimoto

et al. 2015

Journal of Plant Physiology

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“…Therefore, we sought to assess whether overexpression of KDM4A-C proteins affects MSH6 foci during S phase. Toward this end, we used U2OS-TetON cell lines that conditionally express functional EGFP-KDM4A-C fusions upon the addition of doxycycline ( Ipenberg et al, 2013 ; Kupershmit et al, 2014 ). Importantly, the expression levels of EGFP-KDM4A-C fusions are comparable to the levels of the endogenous KDM4A-C proteins found in human breast adenocarcinoma cell line, MCF7, known to have elevated levels of KDM4 proteins ( Berry and Janknecht, 2013 ; Berry et al, 2012 ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway

Awwad

Ayoub

2015

Biology Open

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The KDM4 family of lysine demethylases consists of five members, KDM4A, -B and -C that demethylate H3K9me2/3 and H3K36me2/3 marks, while KDM4D and -E demethylate only H3K9me2/3. Recent studies implicated KDM4 proteins in regulating genomic instability and carcinogenesis. Here, we describe a previously unrecognized pathway by which hyperactivity of KDM4 demethylases promotes genomic instability. We show that overexpression of KDM4A-C, but not KDM4D, disrupts MSH6 foci formation during S phase by demethylating its binding site, H3K36me3. Consequently, we demonstrate that cells overexpressing KDM4 members are defective in DNA mismatch repair (MMR), as evident by the instability of four microsatellite markers and the remarkable increase in the spontaneous mutations frequency at the HPRT locus. Furthermore, we show that the defective MMR in cells overexpressing KDM4C is mainly due to the increase in its demethylase activity and can be mended by KDM4C downregulation. Altogether, our data suggest that cells overexpressing KDM4A-C are defective in DNA MMR and this may contribute to genomic instability and tumorigenesis.

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Heat Shock Protein 90 (Hsp90) Selectively Regulates the Stability of KDM4B/JMJD2B Histone Demethylase

Cited by 30 publications

References 36 publications

GPS2/KDM4A Pioneering Activity Regulates Promoter-Specific Recruitment of PPARγ

GPS2/KDM4A Pioneering Activity Regulates Promoter-Specific Recruitment of PPARγ

Heat shock protein 90 acts in brassinosteroid signaling through interaction with BES1/BZR1 transcription factor

Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway

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