ASXL1 Represses Retinoic Acid Receptor-mediated Transcription through Associating with HP1 and LSD1

Lee, Sang-Wang; Cho, Yang-Sook; Na, Jung-Min; Park, Ui-Hyun; Kang, Myengmo; Kim, Eun-Joo; Um, Soo‐Jong

doi:10.1074/jbc.m109.065862

Cited by 87 publications

(44 citation statements)

References 56 publications

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“…The frequent disruption of ASXL1 domains that are implicated in gene activation (the PHD domain, the RARa-binding domain and the SRC1-binding domain) indicates that only the repressive domains (the HP1-and LSD1-binding domains) remain intact. Although the RARa-binding domain plays a role in RARa-dependent repression, this domain is not required for the RARaindependent repressive capacity of ASXL1 displayed in in vitro assays [13]. Therefore, if expressed, the repressive domains might interfere with epigenetic regulation.…”

Section: The Asxl1 Proteinmentioning

confidence: 98%

“…1a). Subsequent gene silencing involves complex formation with the epigenetic regulators HP1 and LSD1 [13,14], whereas gene activation involves both the C-terminal PHD domain of ASXL1 and the interaction of ASXL1 with the histone methyltransferase SRC1 [15] (Fig. 1a).…”

Section: The Asxl1 Proteinmentioning

confidence: 98%

“…1a) displays a dual function in that it mediates both gene repression and gene activation, depending on the cellular context [13][14][15]. Gene regulation by ASXL1 in mammalian cells is exerted by interaction of ASXL1 with nuclear receptors, like RARa and PPARc, upon ligand induction (Fig.…”

Section: The Asxl1 Proteinmentioning

confidence: 98%

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Mutations in epigenetic regulators in myelodysplastic syndromes

2012

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Until recently, the genetic aberrations that are causally linked to the pathogenesis of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms were largely unknown. Using novel technologies like high-resolution SNP-array analysis and next generation sequencing, various genes have now been identified that are recurrently mutated. Strikingly, several of the newly identified genes (ASXL1, DNMT3A, EZH2, IDH1 and IDH2, and TET2) are involved in the epigenetic regulation of gene expression. Aberrant epigenetic modifications have been described in many types of cancer, including myeloid malignancies. It has been proposed that repression of genes that are crucial for the cessation of the cell cycle and induction of differentiation might contribute to the malignant transformation of normal hematopoietic cells. Several therapies that aim to re-express silenced genes are currently being tested in MDS, like histone deacetylase inhibitors and hypomethylating agents. It will be interesting to assess whether patients carrying mutations in epigenetic regulators respond differently to these novel forms of epigenetic therapies.

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Section: The Asxl1 Proteinmentioning

confidence: 98%

Section: The Asxl1 Proteinmentioning

confidence: 98%

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Mutations in epigenetic regulators in myelodysplastic syndromes

2012

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“…ASXL1 belongs to a three-member family of enhancers of trithorax and polycomb proteins (ASXL1, 2, 3) involved in the maintenance of activation and the silencing of development-related genes through chromatin remodeling [60,61]. The ASXL genes share conserved domains: an aminoterminal ASX homology (ASXH) domain and a C-terminal plant homeodomain (PHD) finger.…”

Section: Asxl1 Mutationsmentioning

confidence: 99%

Molecular aspects of myeloproliferative neoplasms

et al. 2010

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During these past 5 years several studies have provided major genetic insights into the pathogenesis of the so-called classical myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The discovery of the JAK2V617F mutation first, then of the JAK2 exon 12 and MPLW515 mutations, have modified the understanding of these diseases, their diagnosis, and management. Now it is established that almost 100% of PV patients present a JAK2 mutation. Nearly 60% of ET patients and 50% of patients with PMF have the JAK2V617F mutation. The MPLW515 mutations are also present in a small proportion of ET and PMF patients. These mutations are oncogenic events that cause these disorders; however, they do not explain the heterogeneity of the entities in which they occur. Genetic defects have not been yet identified in around 40% of ET and PMF. There are likely additional somatic genetic factors important for the MPN phenotype like the recently described TET2, ASXL1, and CBL mutations. Moreover, polymorphisms in the JAK2 gene have been recently described as associated with MPN. Additional studies of large cohorts are required to dissect the genetic events in MPNs and the mechanisms of these oncogenic cooperations.

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“…The ASXL1 belongs to the enhancer of trithorax and Polycomb group genes which encode proteins characterized by N-terminal helix-turn-helix domain HARE-HTH and C-terminal PHD (Plant Homeo Domain) finger [1,2]. The encoded ASXL1 protein is required for both maintenance of activation and silencing of Polycomb group (PcG) proteins and their antagonists, trithorax group (trxG), including repression of retinoic acid receptor-mediated transcription [3]. PcG and trxG proteins display highly conserved functional mechanisms, ensuring epigenetic maintenance of gene expression patterns through mitosis and faithful propagation of cell fates.…”

Section: Introductionmentioning

confidence: 99%