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PubMed2003

Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus.

A comprehensive analysis of 53 penile carcinomas was performed to determine which mechanisms might be involved in the disruption of the p16(INK4A)/cyclin D/Rb pathway. To that end, human papillomavirus (HPV) presence, p16(INK4A) expression and promoter methylation, and expression of the BMI-1 polycomb gene product were studied. Sixteen (30%) of the carcinomas were found to harbour high-risk HPV DNA, 15 of which contained HPV 16. HPV 16 E6/E7 oncogene transcripts were detected in 13 (87%) of the carcinomas that contained HPV 16. Strong immunostaining for p16(INK4A) was significantly more frequent in carcinomas that contained high-risk HPV DNA (p < 0.001) and amongst those with HPV 16 DNA, it was more frequent in lesions in which E6/E7 transcripts were detectable (p = 0.029). This supports an active role for HPV E7 in interfering with the p16(INK4A)/cyclin D/Rb pathway. Methylation of the p16(INK4A) promoter or overexpression of the BMI-1 polycomb gene product may provide alternative modes of interference with this pathway. These phenomena were mutually exclusive and found in the absence of HPV in 15% and 10% of the penile carcinomas, respectively. These data indicate that there are at least three plausible mechanisms by which the p16(INK4A)/cyclin D/Rb pathway can become disrupted during penile carcinogenesis.

Adult↗
PubMed1997

Membrane binding and enzymatic activation of a Dbl homology domain require the neighboring pleckstrin homology domain.

Dbl-homology (DH) domains are invariably located immediately N-terminal to a pleckstrin homology (PH) domain. To understand the functional relationship between these two domains we expressed the DH domain alone, the PH domain alone, and the DH-PH combination of the invasion inducing protein Tiam-1 fused to glutathione-S-transferase (GST) or green fluorescent protein (GFP). We found that the GST-DH-PH and the GST-PH constructs bind to preparations of brain membranes and to the beta gamma subunits of trimeric G proteins in vitro, while the GST-DH and GST control do not. The GFP-DH-PH and GFP-PH constructs are localized to peripheral membranes of COS-7 cells in vivo, while GFP and GFP-DH domain constructs are found diffusely in the cytoplasm. The DH-PH domain combination activates Jun N-terminal kinase (JNK) strongly, but the DH domain alone and the PH domain alone have little effect. We conclude that membrane localization and enzymatic activation of the DH domain require the adjacent PH domain.

Animals↗
PubMed1999

Characterization of cis-elements required for the transcriptional activation of the rae28/mph1 gene in F9 cells.

The rae28/mph1 gene is the mouse homologue of the Drosophila polyhomeotic gene, which plays a crucial role in the maintenance of the transcriptional repression state of Hox genes. Expression of the rae28/mph1 gene is induced during retinoic acid (RA)-mediated differentiation of embryonal carcinoma F9 cells. By transient-transfection experiments, we identified a pair of inverted differentiation response sequences (DRS(s)) in the 5' flanking region. Each of the DRS(s) contained the consensus sequence [5'-CCTCCCCXCXGCCCCCTCCXCXC-3'], which is also conserved in the human counterpart of the rae28/mph1 gene. Electrophoretic mobility shift assay and DNase I foot printing with nuclear extracts derived from F9 cells demonstrated the presence of novel DNA-binding factors which specifically interact with DRS(s). Nucleotide substitutions in the 3' DRS abrogated the factor binding and the transcriptional activation, suggesting that DRS(s) and DRS-binding factors play an important role in the transcriptional regulation of the rae28/mph1 gene.

Animals↗
PubMed2002

Alternative transcripts of a polyhomeotic gene homolog are expressed in distinct regions of somites during segmentation of zebrafish embryos.

Here we describe isolation and characterization of two zebrafish cDNAs, designated ph2alpha and ph2beta, which were identified as structural homologs of the Drosophila polyhomeotic, mouse Mph2, and human HPH2 genes, collectively termed the Polycomb group. The alpha and beta transcripts shared a 1.9-kb sequence at their 3'-termini. Alpha had an additional 1.6-kb sequence extending toward its 5'-terminus. Only a short 0.1-kb segment was unique to beta. Sequencing of a genomic clone corresponding to the two cDNAs indicated that the mRNAs were transcribed from a single gene locus by alternative promoters. Northern blots revealed expression of alpha transcripts during the segmentation period, while beta expression occurred at all developmental stages examined. Whole-mount in situ hybridizations with an alpha-specific probe and a probe recognizing both transcripts revealed distinct spatio-temporal expression patterns along developing somites. Alpha transcripts were detected initially at the 7-8 somite stage; beta transcripts appeared in the first somites. As segmentation proceeded, alpha and beta expression shifted position toward the tailbud in parallel with the formation of each somite. Within individual somites, the signal corresponding to alpha was strongest at the posterior border and weakest in the anterior region. Conversely, that corresponding to beta was strongest at the anterior border and weakest in the posterior region. The data support the idea that Ph2alpha and Ph2beta are involved in spatio-temporal generation of somites as well as in specification of antero-posterior regional differences within individual somites.

Amino Acid Sequence↗
PubMed1997

Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes.

A cosmid contig was constructed from a YAC clone with a 220-kb insert that spans the centromeric side of the human MHC class II region, corresponding to the mouse t complex. The gene order was identified to be HSET-HKE1.5-HKE2-HKE3-RING1-HKE6- HKE4 (RING5). The genomic sequence of a 42,801-bp long region encoded by one cosmid clone in the RING1, HKE6, and HKE4 subregions was determined by the shotgun method. The exon-intron organization of these three genes, RING1 (Ring finger protein), HKE6 (steroid dehydrogenase-like protein), and HKE4 (transmembrane protein with histidine-rich charge clusters), was determined. The previously reported RING2 gene was revealed to be identical to HKE6. Transcripts from HKE4 were detected in the placenta, lung, kidney, and pancreas. Those of HKE6 were found in the liver and pancreas. The 25-kb region proximal to the RING1 gene includes an extensive dense cluster of Alu repeats (about 1.2 Alu per kb), and no gene has been identified in this so far. The region is equivalent to part of the mouse t complex and could be of relevance to human development.

Amino Acid Sequence↗
PubMed2005

Epigenetic inheritance of chromatin states mediated by Polycomb and trithorax group proteins in Drosophila.

Proteins of the Polycomb group (PcG) and of the trithorax group (trxG) are involved in the regulation of key developmental genes, such as homeotic genes. PcG proteins maintain silent states of gene expression, while the trxG of genes counteracts silencing with a chromatin opening function. These factors form multimeric complexes that act on their target chromatin by regulating post-translational modifications of histones as well as ATP-dependent remodelling of nucleosome positions. In Drosophila, PcG and trxG complexes are recruited to specific DNA elements named as PcG and trxG response elements (PREs and TREs, respectively). Once recruited, these complexes seem to be able to establish silent or open chromatin states that can be inherited through multiple cell divisions even after decay of the primary silencing or activating signal. In recent years, many components of both groups of factors have been characterized, and the molecular mechanisms underlying their recruitment as well as their mechanism of action on their target genes have been partly elucidated. This chapter summarizes our current knowledge on these aspects and outlines crucial open questions in the field.

Animals↗
PubMed2006

Polycomb silencing mechanisms and genomic programming.

Polycomb complexes, best known for their role in the epigenetic silencing of homeotic genes, are now known to regulate a large number of functions in organisms from flies to man. They control transcription activators, pattern-forming genes, maintenance of stem cells and are implicated in cell proliferation and oncogenesis. Our understanding of Polycomb mechanisms derives principally from the study of homeotic genes in Drosophila, where they act in an all-or-none fashion to silence expression in inappropriate parts of the organism. This review summarizes what has been learned from homeotic genes and examines the possible extensions of Polycomb mechanisms to allow for dynamic regulatory behavior and the reprogramming of silenced chromatin states.

Animals↗
PubMed2005

Polycomb gene product Bmi-1 regulates stem cell self-renewal.

The Polycomb group (PcG) gene Bmi-1 has recently been implicated in the maintenance of hematopoietic stem cells (HSCs). However, the role of each component of PcG complex in HSCs and the impact of forced expression of PcG genes on stem cell self-renewal remain to be elucidated. To address these issues, we performed both loss-of-function and gain-of-function analysis on various PcG proteins. Expression analysis revealed that not only Bmi-1 but also other PcG genes are predominantly expressed in HSCs. Loss-of-function analyses, however, demonstrated that absence of Bmi-1 is preferentially linked with a profound defect in HSC self-renewal, indicating a central role for Bmi-1, but not the other components, in the maintenance of HSC self-renewal. Over-expression analysis of PcG genes also confirmed an important role of Bmi-1 in HSC self-renewal. Our findings indicate that the expression level of Bmi-1 is the critical determinant for the self-renewal capacity of HSCs. These findings uncover novel aspects of stem cell regulation exerted through epigenetic modifications by the PcG proteins.

Animals↗
PubMed1995

Characterization of a region of the X chromosome of Drosophila including multi sex combs (mxc), a Polycomb group gene which also functions as a tumour suppressor.

Genetic analysis of the 8D3;8D8-9 segment of the Drosophila melanogaster X chromosome has assigned seven complementation groups to this region, three of which are new. A Polycomb group (Pc-G) gene, multi sex combs (mxc), is characterized and mutant alleles are described. Besides common homeotic transformations characteristic of Pc-G mutants that mimic the ectopic gain of function of BX-C and ANT-C genes, mxc mutants show other phenotypes: they zygotically mimic, in males and females, the characteristic lack of germ line seen in progeny of some maternal effect mutants of the so-called posterior group (the grandchildless phenotype). Loss of normal mxc function can promote uncontrolled malignant growth which indicates a possible relationship between Pc-G genes and tumour suppressor genes. We propose that gain-of-function of genes normally repressed by the wild-type mxc product could, in mxc mutants, give rise to an incoherent signal which would be devoid of meaning in normal development. Such a signal could divert somatic and germ line development pathways, provoke the loss of cell affinities, but allow or promote growth.

Alleles↗
PubMed1995

Mapping functional domains of the polycomb protein of Drosophila melanogaster.

In Drosophila the Polycomb group (Pc-G) proteins are responsible for the stable and heritable silencing of genes. The Pc-G apparently uses heterochromatin-like mechanisms to transcriptionally inactivate developmental regulators such as the homeotic genes. The Polycomb (Pc) protein is part of a large multimeric complex composed of other members of the Pc-G. We have identified functionally relevant domains of the Pc protein by sequencing different Pc alleles. Additionally, using a Pc-beta gal fusion protein with deleted internal histidine repeats, we found that this mutant protein cannot bind to four particular target loci, but otherwise does not change the remaining overall binding pattern. We show that, in contrast to the dotted subnuclear localization of the wild-type protein, the nuclear distribution of mutant proteins becomes homogeneous. Surprisingly, in Pc mutants the polyhomeotic protein, another member of the Pc-G, is also redistributed in the nucleus. Our results indicate that the appropriate subnuclear localization of the two proteins is critical for the silencing function of the Pc-G complex.

Alleles↗
PubMed1996

Interactions between cut wing mutations and mutations in zeste, and the enhancer of yellow and Polycomb group genes of Drosophila melanogaster.

The phenotypic expression of several mutations in the cut locus of Drosophila melanogaster is modified by mutations in the zeste, e(y)2 and e(y)3 genes and in some genes of the Polycomb group. All tested sensitive cut mutations have a partially inactivated cut wing enhancer. e(y)3u1, Zv77h and Su(z)2(5) mutations enhance, while e(y)2u1, ZOp6, PSC1, Su(z)301, Su(z)302 and ScmD1 mutations suppress the ct mutant phenotype. The results are discussed in terms of the role of long-distance interactions and DNA compaction in transcriptional control of the cut locus.

Animals↗
PubMed2002

Mutation analysis of the mel-18 gene that shows decreased expression in human breast cancer cell lines.

BACKGROUND: Mammalian mel-18 is a member of the polycomb group, and it acts as a transcriptional repressor with DNA binding activity. Murine mel-18 negatively regulates the cell cycle through the c-myc/cdc25 cascade, and mice haploinsufficient for mel-18 develop mammary gland tumors. In addition, the human homolog of mel-18 is located at 17q, on which candidate tumor suppressor genes for breast cancer have been suggested for a long time. These observations indicate that the mel-18 gene may be a tumor suppressor gene for breast cancer. To investigate this possibility, we examined the expression of mel-18 mRNA in human breast cancer cell lines and searched for mel-18 gene mutations in sporadic and familial breast cancers. METHODS: The expression of mel-18 mRNA was examined in five breast cancer cell lines by RT-PCR, and somatic and germline mutations of the mel-18 gene were analyzed by the PCR-SSCP and sequence methods in 48 sporadic breast cancers, including 16 cases with loss of heterozygosity (LOH) at the mel-18 locus, and in 23 cases from 18 breast cancer families, respectively. RESULTS: We found that most cell lines examined here showed decreased expression of mel-18 mRNA, however, no alteration other than a single nucleotide change that did not lead to amino acid alteration in one patient was identified. CONCLUSION: Our results reveal that mel-18 gene mutations are exceedingly rare in human breast cancers, and a reduction of mel-18 expression in human breast cancer cell lines would support a role for mel-18 haploinsufficiency in breast carcinogenesis.

Adult↗
PubMed1998

Functional analysis of mouse Polycomb group genes.

Two groups of genes, the Polycomb group (Pc-G) and trithorax group (trx-G), have been identified in Drosophila to provide a transcriptional memory mechanism. They ensure the maintenance of transcription patterns of key regulators such as the Hox genes and thereby the correct execution of developmental programmes. Recent data suggest that this memory mechanism is conserved in vertebrates and plants. Here we discuss current insights into the role of mouse Pc-G genes, with a particular focus on the best-studied Bmi1, Mel18 and M33 genes, as representative examples. Common phenotypes observed in knockout mice mutant for each of these genes indicate an important role for Pc-G genes not only in regulation of Hox gene expression and axial skeleton development but also in control of proliferation and survival of haematopoietic cell lineages. Proliferation defects are also observed in other cell lineages derived from these null-mutant mice, and provide new tools to study the impact of Pc-G deregulation on cell cycle control.

Animals↗
PubMed2005

Bmi1 in development and tumorigenesis of the central nervous system.

The role of the Polycomb group gene Bmi1 in proliferation control of lymphoid and neuronal progenitors as well as in self-renewal of haematopoietic and neural stem cells has been recently demonstrated. Here we review these recent findings with particular regard to their implications for central nervous system development and tumorigenesis.

Central Nervous System↗
PubMed1999

The nuclear distribution of Polycomb during Drosophila melanogaster development shown with a GFP fusion protein.

The chromatin protein Polycomb (PC) is necessary for keeping homeotic genes repressed in a permanent and heritable manner. PC is part of a large multimeric complex (PcG proteins) involved in generating silenced chromatin domains at target genes, thus preventing their inappropriate expression. In order to assess the intranuclear distribution of PC during mitosis in different developmental stages as well as in the germ line we generated transgenic fly lines expressing a PC-GFP (Green Fluorescent Protein) fusion protein. Rapidly dividing nuclei were found to display a rather homogeneous PC-GFP distribution. However, with increasing differentiation a pronounced subnuclear pattern was observed. In all investigated diploid somatic tissues the bulk of PC-GFP fusion protein is depleted from the chromosomes during mitosis: however, a detectable fraction remains associated. In the male germ line in early spermatogenesis, PC-GFP was closely associated with the chromosomal bivalents and gradually lost at later stages. Interestingly, we found that PC is associated with the nucleolus in spermatocytes, unlike somatic nuclei. In contrast to mature sperm showing no PC-GFP signal the female germ line retains PC in the germinal vesicle.

Animals↗
PubMed2001

Ectopic expression of BEAF32A in the Drosophila eye imaginal disc inhibits differentiation of photoreceptor cells and induces apoptosis.

Transgenic flies were established in which ectopic expression of boundary element-associated factor (BEAF) 32A was targeted to the Drosophila eye imaginal disc. The eyes of the adult fly displayed a severe rough eye phenotype. When these eyes were sectioned, most ommatidia were found to be fused and irregularly shaped rhabdomeres were observed. In the developing eye imaginal disc, expression of BEAF32A inhibited differentiation of photoreceptor cells. Expression of BEAF32A also induced extensive apoptosis of eye imaginal disc cells and, consistent with this, co-expression of baculovirus P35 in the eye imaginal disc suppressed the BEAF32A-induced rough eye phenotype. To investigate the effects of BEAF32A on regulation of chromatin structure, genetic crosses of the BEAF32A-overexpressing flies with loss-of-function mutants for genes encoding other boundary element-binding factors or regulators of chromatin structure were conducted. Interestingly, half-dose reduction of the su(Hw) gene strongly enhanced the rough eye phenotype induced by BEAF32A. Furthermore, genetic crosses of the transgenic flies with loss-of-function mutants for genes interacting with Polycomb revealed specific links between BEAF32A and genes such as Distalless and kohtalo, suggesting a relation to the chromatin insulator function of BEAF. In addition, genetic crosses of transgenic flies expressing BEAF32A with a collection of Drosophila deficiency stocks allowed us to identify several genomic regions, deletions of which caused enhancement or suppression of the BEAF32A-induced rough eye phenotype. The transgenic flies established in this study should be useful to identify targets of BEAF32A and its positive or negative regulators in Drosophila.

Animals↗
PubMed1999

The Additional sex combs gene of Drosophila is required for activation and repression of homeotic loci, and interacts specifically with Polycomb and super sex combs.

The protein products of Polycomb group (PcG) and trithorax group (trxG) genes are required for the maintenance of the transcriptionally repressed and active states, respectively, of the homeotic genes. Mutations in PcG genes produce gain-of-function (posterior) homeotic transformations, while mutations in trxG genes produce loss-of-function (anterior) homeotic transformations. Double mutant combinations between a PcG gene and a trxG gene suppress the homeotic transformations seen with either mutation alone, suggesting that PcG and trxG genes act antagonistically. The PcG gene Additional sex combs (Asx) is interesting because one mutant allele, AsxP1, causes both anterior and posterior homeotic transformations. AsxP1 and other Asx mutations were crossed to mutations in the PcG gene Polycomb (Pc) and the trxG gene trithorax (trx). Asx alleles enhance both PcG and trxG homeotic transformations, showing that Asx is required for both the activation and the repression of homeotic loci. Asx also shows strong allele-specific interactions with the PcG genes Pc and super sex combs (sxc). Together, these data indicate that there are functional interactions between Asx, Pc and sxc in vivo. ASX may interact with a PcG complex containing PC and SXC and mediate activation versus repression at target loci, perhaps by interacting directly with the TRX protein.

Alleles↗