RAE28, BMI1, and M33 Are Members of Heterogeneous Multimeric Mammalian Polycomb Group Complexes

Hashimoto, Naoko; Brock, Hugh W.; Nomura, Midori; Kyba, Michael; Hodgson, Jacob W.; Fujita, Yuzuru; Takihara, Yoshihiro; Shimada, Kazunori; Higashinakagawa, Toru

doi:10.1006/bbrc.1998.8438

Cited by 64 publications

(58 citation statements)

References 44 publications

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“…When expressed alone (data not shown) or in conjunction with AF9,¯uorescent protein-tagged MPc3 is found distributed throughout the nucleus in small punctate structures ( Figure 3). This pattern is strikingly similar to other PcG proteins that have been analysed by immuno¯uorescence microscopy (Alkema et al, 1997a, b;Gunster et al, 1997;Schoorlemmer et al, 1997;Hashimoto et al, 1998). Like MPc3, tagged AF9 is localized to the nucleus and also assumes a punctate pattern of distribution.…”

Section: Mpc3 and Af9 Co-localize In The Nuclei Of Nih3t3 Cellssupporting

confidence: 81%

“…However, characterization of both¯y and mammalian PcG proteins indicates that the individual PcG proteins contain one or more domains that mediate binding to other PcG proteins. Thus multiple protein ± protein contacts appear to be made within a PcG complex serving to stabilize the structure through mutual interactions (Alkema et al, 1997a;Gunster et al, 1997;Peterson et al, 1997;Schoorlemmer et al, 1997;Hashimoto et al, 1998;Hemenway et al, 1998). These ®ndings are consistent with the long-standing observation that single PcG gene mutations produce a relatively mild phenotype while multiple mutations act synergistically to produce severe developmental anomalies.…”

Section: Introductionsupporting

confidence: 63%

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The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias

2001

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Polycomb group (PcG) proteins assemble to form large multiprotein complexes involved in gene silencing. Evidence suggests that PcG complexes are heterogeneous with respect to both protein composition and speci®c function. MPc3 is a recently described mouse Polycomb (Pc) protein that shares structural homology with at least two other Pc proteins, M33 and MPc2. All three Pc proteins bind another PcG protein, RING1, through a conserved carboxy-terminal C-box motif. Here, data are presented demonstrating that MPc3 also interacts with AF9, a transcriptional activator implicated in the development of acute leukemias. The carboxy-terminus of AF9 is fused to the MLL protein in leukemias characterized by t(9;11)(p22;q23) chromosomal translocations. Importantly, it is the carboxy-terminus of AF9 to which MPc3 binds. The AF9 binding site of MPc3 maps to a central, non-conserved, region of the polypeptide sequence. In contrast to MPc3, data indicate that the Pc protein M33 does not interact with AF9. This ®nding suggests a potentially unique role for MPc3 in linking a PcG silencing complex to a transcriptional activator protein. Oncogene (2001) 20, 3798 ± 3805.

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Section: Mpc3 and Af9 Co-localize In The Nuclei Of Nih3t3 Cellssupporting

confidence: 81%

Section: Introductionsupporting

confidence: 63%

The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias

2001

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“…[4][5][6][7][8] MEL18, BMI1, RING1, RNF2, HPH1, HPH2, HPC1, HPC2 and HPC3 are members of this complex. Recent studies identify a PRC1-like complex as the H2A ubiquitin ligase, linking H2A ubiquitination to PcG silencing.…”

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confidence: 99%

Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays

et al. 2006

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In spite of the known function of polycomb group (PcG) genes in stem cell self-renewal, control of cellular proliferation and differentiation, its role in cancer pathogenesis is still poorly understood. We studied the expression by immunohistochemistry of several PcG-maintenance complex proteins (RING1, RNF2, BMI1, MEL18, HPH1 and RYBP) in nontumoral (154 samples) and tumoral (550 samples) human tissues using Tissue Microarrays. For selected genes (BMI1 and RING1) FISH analysis has been also carried out. PcG proteins had a tissue-and cell-type-specific expression pattern. Some of them were highly selectively expressed, such as HPH1, which was detected in germ cells in testis, pituitary and parathyroid glands and Langerhans islets, and RYBP, which was found in placenta, umbilical cord and thyroid gland. By contrast, RING1 was ubiquitously expressed in every normal tissue analyzed. Changes in expression associated with tumoral transformation have been found for BMI1 and RNF2, which exhibited increased expression in a large series of tumors, including gastrointestinal tumors, pituitary and parathyroid adenomas, and lymphomas, compared with their expression in normal-cell counterparts. The high level of expression of BMI1 protein observed in mantle-cell lymphomas and pituitary adenomas is associated in some cases with amplification of BMI1 locus. These findings imply that upregulation of BMI1 may constitute a malignancy marker in different types of cancer, mainly in lymphoid and endocrine tumors. RING1 was lost in a group of renal-cell carcinomas and testicular germ-cell tumors. Lastly, RYBP is anomalously expressed in Hodgkin's lymphomas and oligodendrogliomas, among others tumors. A significant finding of the study is the identification of unique PcG profiles for some tumors, such as testicular germ-cell tumors, which have high levels of HPH1 expression and loss of RING1 and/ or BMI1; pituitary adenomas, which expressed every PcG protein analyzed; and clear-cell renal-cell carcinoma, which was the only tumor other than testicular germ-cell tumors that did not express RING1.

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“…PcG proteins associate with each other through conserved domains and form multimeric complexes (Alkema et al, 1997;Hashimoto et al, 1998;Takihara and Hara, 2000;Tomotsune et al, 1999). There exist at least two classes of PcG complexes, PcG complexes 1 and 2 (Takihara and Hara, 2000).…”

mentioning

confidence: 99%

“…There exist at least two classes of PcG complexes, PcG complexes 1 and 2 (Takihara and Hara, 2000). PcG complex 1 consists of multimeric complexes, including PcG family members, M33, bmi1, mel18, and rae28 (also designated as mph1), mph2, and Scmh1 (Alkema et al, 1997;Hashimoto et al, 1998;Tomotsune et al, 1999) and may be a homolog to Drosophila Polycomb repressive complex 1, which competitively antagonizes the ATP-dependent nucleosome remodeling ability of SWI/SNF family complexes (Shao et al, 1999). PcG complex 2 is distinct from PcG complex 1 and includes eed and Enx1/EZH2 or Enx2 (Takihara and Hara, 2000).…”

mentioning

confidence: 99%

Overexpression of Polycomb-Group Gene rae28 in Cardiomyocytes Does Not Complement Abnormal Cardiac Morphogenesis in Mice Lacking rae28 But Causes Dilated Cardiomyopathy

Koga

Kaji

Nishii

et al. 2002

Laboratory Investigation

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SUMMARY:The Polycomb-group genes (PcG) are widely conserved from Drosophila to mammals and are required for maintaining positional information during development. The rae28 gene (rae28) is a member of the mouse PcG. Mice deficient in rae28 (rae28 Ϫ/Ϫ ) demonstrated that rae28 has a role not only in anteroposterior patterning but also in cardiac morphogenesis. In this study we generated transgenic mice with ubiquitous or cardiomyocyte-specific exogenous rae28 expression. Genetic complementation experiments with these transgenic mice showed that ubiquitous expression of rae28 could reverse the cardiac anomalies in rae28 Ϫ/Ϫ , whereas cardiomyocyte-specific expression of rae28 could not, suggesting that rae28 is involved in cardiac morphogenesis through a noncardiomyocyte pathway. Interestingly, however, cardiomyocyte-specific overexpression of rae28 caused dilated cardiomyopathy, which was associated with cardiomyocyte apoptosis, abnormal myofibrils, and severe heart failure. Cardiac expression of rae28 was predominant in the early embryonic stage, whereas that of the other PcG members was relatively constitutive. Because rae28 forms multimeric complexes with other PcG proteins in the nucleus, it is presumed that constitutive cardiomyocyte-specific rae28 overexpression impaired authentic PcG functions in the heart. rae28-induced dilated cardiomyopathy may thus provide a clue for clarifying the direct role of PcG in the maintenance of cardiomyocytes. (Lab Invest 2002, 82:375-385).

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RAE28, BMI1, and M33 Are Members of Heterogeneous Multimeric Mammalian Polycomb Group Complexes

Cited by 64 publications

References 44 publications

The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias

The polycomb protein MPc3 interacts with AF9, an MLL fusion partner in t(9;11)(p22;q23) acute leukemias

Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays

Overexpression of Polycomb-Group Gene rae28 in Cardiomyocytes Does Not Complement Abnormal Cardiac Morphogenesis in Mice Lacking rae28 But Causes Dilated Cardiomyopathy

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