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At least 1,387 records · Page 77Linked to original sources
PubMed1999

Spo76p is a conserved chromosome morphogenesis protein that links the mitotic and meiotic programs.

Spo76p is conserved and related to the fungal proteins Pds5p and BIMD and the human AS3 prostate proliferative shutoff-associated protein. Spo76p localizes to mitotic and meiotic chromosomes, except at metaphase(s) and anaphase(s). During meiotic prophase, Spo76p assembles into strong lines in correlation with axial element formation. As inferred from spo76-1 mutant phenotypes, Spo76p is required for sister chromatid cohesiveness, chromosome axis morphogenesis, and chromatin condensation during critical transitions at mitotic prometaphase and meiotic midprophase. Spo76p is also required for meiotic interhomolog recombination, likely at postinitiation stage(s). We propose that a disruptive force coordinately promotes chromosomal axial compaction and destabilization of sister connections and that Spo76p restrains and channels the effects of this force into appropriate morphogenetic mitotic and meiotic outcomes.

Amino Acid Sequence↗
PubMed2003

Constitutive phosphorylation of FKHR transcription factor as a prognostic variable in acute myeloid leukemia.

The transcription factor FKHR, which is controlled by Akt-PKB signaling, is involved in regulating cell cycle progression and cell death. In this study, the phosphorylation of FKHR was observed in 45 (73.8%) of 61 patients with acute myeloid leukemia (AML). The phosphorylation of Akt-PKB was found to be significantly associated with phospho-FKHR (P<0.001). Patients with phospho-FKHR had a significantly shorter overall survival than those without (P<0.05). In conclusion, the constitutive phosphorylation of FKHR was observed in the majority of AML, and the detection of phospho-FKHR might provide a new tool for identifying AML patients with an unfavorable outcome.

Acute Disease↗
PubMed2000

Concomitant amplification and expression of PAX7-FKHR and MYCN in a human rhabdomyosarcoma cell line carrying a cryptic t(1;13)(p36;q14).

Alveolar rhabdomyosarcoma (ARMS) is associated with the specific chromosomal translocation (2;13)(q35;q14) or its rarer variant t(1;13)(p36;q14), which produces the fusion gene PAX7-FKHR. Here we describe the human cell line RC2, derived from an ARMS, which harbors a cryptic t(1;13)(p36;q14) and concomitantly shows amplification of the PAX7-FKHR fusion gene and of the MYCN oncogene. The t(1;13) and MYCN oncogene were studied by standard cytogenetic analysis and molecular techniques. The reverse transcriptase polymerase chain reaction demonstrated the expression of PAX7-FKHR mRNA in RC2 cells, although karyotype analysis failed to demonstrate a t(1;13)(p36;q14) chromosomal translocation or a derivative 13 chromosome. Double minute chromosomes were detected in all the metaphases studied. Fluorescence in situ hybridization analysis revealed multiple copies of the PAX7-FKHR fusion gene localized exclusively on a subset of double minutes, whereas multiple copies of MYCN were identified on other double minute chromosomes. Southern-blot analysis demonstrated that RC2 cells contain approximately 20 copies of the MYCN oncogene. So far no continuous RMS cell line carrying the t(1;13)(p36;q14) has been described, and PAX7-FKHR and MYCN amplifications have always been reported to occur separately in rhabdomyosarcoma (RMS). The availability of an ARMS cell line that harbors the t(1;13)(p36;q14) constitutes a useful tool for further understanding the role of the PAX7-FKHR fusion gene in RMS oncogenesis and may improve knowledge of the possible relation between PAX7-FKHR and MYCN amplification.

Chromosomes, Human, Pair 1↗
PubMed2003

Chromosomal imbalances in pleomorphic rhabdomyosarcomas and identification of the alveolar rhabdomyosarcoma-associated PAX3-FOXO1A fusion gene in one case.

Rhabdomyosarcomas (RMS) are soft tissue sarcomas resembling developing skeletal muscle, and pleomorphic rhabdomyosarcomas (PRMS) are a rare nonpediatric entity. Little molecular cytogenetic information exists for PRMS, and their relationship to other subtypes of rhabdomyosarcoma and other sarcomas is unclear. Chromosomal imbalances were determined in seven well-characterized cases of PRMS using comparative genomic hybridization. The smallest overlapping regions of gain were 1p22 approximately p33 (71%), 7p (43%), 18/18q (43%), and 20/20p (43%), and the regions of loss were 10q23 (71%), 15q21 approximately q22 (57%), 3p, 5q32 approximately qter, and 13 (all 43%). Four of the seven cases had amplicons involving the regions 1p21 approximately p31, 1q21 approximately q25, 3p12, 3q26 approximately qtel, 4q28 approximately q31, 8q21 approximately q23/8q, and 22q. These regions are distinct from those frequently associated with the alveolar subtype, whereas the embryonal subtype without anaplasia is rarely associated with amplification events other than gain/amplification of 8q material. The regions of imbalance appeared more similar to those reported for malignant fibrous histiocytomas (MFH) and osteosarcomas, consistent with the suggestion that PRMS can be considered part of the spectrum of MFH. In addition, one of the cases classified as PRMS showed evidence for the presence of a PAX3-FOXO1A fusion gene, which is characteristic of the alveolar subtype of RMS.

Aged↗
PubMed2003

Characterization of the A673 cell line (Ewing tumor) by molecular cytogenetic techniques.

The A673 cell line was established from a patient with a primary rhabdomyosarcoma (RMS), which is referred to in the literature either as a Ewing tumor (ET) or as RMS. Although the two tumoral types are associated with specific and well-characterized translocations, no cytogenetic report on this cell line has been published. We characterized the A673 cell line using a combination of spectral karyotyping (SKY), fluorescence in situ hybridization (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR), which revealed the presence of a complex karyotype and a translocation involving chromosomes 11 and 22 and the fusion of EWS and FLI1 genes, both events being specific to ET. Neither cytogenetics nor molecular alterations specific to RMS were found.

Chromosome Aberrations↗
PubMed2003

Cytogenetic and molecular findings related to rhabdomyosarcoma. An analysis of seven cases.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Histologically, it is subdivided histologically into two main subtypes: alveolar (ARMS) and embryonal (ERMS). ARMS is characterized by t(2;13)(q35;q14) or its variant t(1;13)(p36;q14), which fuse PAX3 and PAX7, respectively, with FKHR to produce chimeric genes. ERMS is frequently associated with loss of heterozygosity of 11p15.5. We investigated seven RMS (three ARMS and four ERMS) by means of cytogenetic, fluorescence in situ hybridization, and molecular analyses, including the study of the main genes implicated in the G1- to S-phase cell cycle transition, and correlated these studies with pathologic findings and clinical outcome. All tumors showed clonal, numerical, and structural chromosomal abnormalities. Two ARMS had the t(2;13)(q35;q14) and the third a PAX7/FKHR fusion, a cryptic t(1;13)(p36;q14), undetected by cytogenetic techniques, but revealed by reverse transcriptase polymerase chain reaction. One ERMS showed a der(11)t(3;11)(p21;p15) as a sole structural anomaly. Gene amplification was seen in four tumors, as double minutes or in the form of homogeneously staining regions. Overexpression of MYCN oncogene was found in two ARMS; N-myc DNA probe detected oncogene amplification located on the double minutes of these cases. Analysis of the regulatory genes responsible for G1- to S-phase transition showed a homozygous deletion of the 9p21 locus genes in a spindle-cell ERMS.

Child↗
PubMed1998

Structural analysis of PAX3 genomic rearrangements in alveolar rhabdomyosarcoma.

In the pediatric cancer alveolar rhabdomyosarcoma, the (2;13)(q35;q14) translocation juxtaposes PAX3 and FKHR to produce a chimeric PAX3-FKHR gene. With the use of Southern blot methodology, genomic rearrangements of PAX3 intron 7 were detected in 23 of 23 fusion-positive alveolar rhabdomyosarcomas and were not detected in 19 fusion-negative embryonal rhabdomyosarcomas. Rearrangements corresponding to the reciprocal FKHR-PAX3 fusion were detected in 21 of 23 PAX3-FKHR-positive cases, though FKHR-PAX3 transcripts were detected in only 15 of 23 cases. Mapping experiments demonstrated that breakpoints occurred throughout this 17.5 kb PAX3 intron and, in 12 of 23 cases, breakpoints clustered within a 4.5-kb region at the 3' end of the intron. Chromatin analysis revealed a prominent DNase I hypersensitive site at the 5' end of the intron but did not indicate any other DNA-protein interactions that might have affected the breakpoint distribution. Sequence analysis identified AT-rich regions within the 3' cluster, as well as alternating purine-pyrimidine and homopyrimidine elements at the borders of this cluster. These finding suggest that translocation breakpoints are constrained to PAX3 intron 7 primarily by functional boundaries related to the flanking exons and may be secondarily affected by sequence features within this intron.

Chromosomes, Human, Pair 13↗
PubMed1998

Normal and rearranged PAX3 expression in human rhabdomyosarcoma.

PAX3, a member of the PAX-gene family, encodes a nuclear transcription factor that is transiently expressed in the neural tube and in muscle progenitor cells and regulates embryonal development in the mouse. Together with the FKHR gene it is involved in the t(2;13)(q35;q14), a specific translocation associated with alveolar rhabdomyosarcoma (ARMS). As a consequence of the rearrangement two chimeric transcripts originate: FKHR-PAX3 and PAX3-FKHR. We studied the expression of wild type PAX3 and the chimeric transcripts originating from the t(2;13) in a series of 23 rhabdomyosarcomas (RMS) of childhood, by reverse transcriptase polymerase chain reaction (RT-PCR). Wild type PAX3 was detected in 48% of the RMS, whereas another 39% were positive only after nested PCR. Normal adult-skeletal muscle showed a very weak expression of PAX3, but fetal muscle did not express PAX3. PAX3-FKHR was found in 11 of 15 alveolar RMS, 7 of which were positive also for the reciprocal transcript, whereas no RMS expressed FKHR-PAX3 alone. These results confirm that the PAX3-FKHR transcript is specifically associated with the alveolar RMS and that it is a more sensitive marker of the t(2;13) than the reciprocal product FKHR-PAX3. Furthermore, the finding of PAX3 expression with or without PAX3-FKHR transcript in the great majority of the cases raises the question of whether PAX3 expression could play a role in the pathogenesis of RMS.

Adult↗
PubMed2000

Structural analysis of PAX7 rearrangements in alveolar rhabdomyosarcoma.

In the pediatric cancer alveolar rhabdomyosarcoma, the common 2;13 and less frequent 1;13 translocations fuse PAX3 and PAX7, respectively, with FKHR to produce chimeric genes. To compare structural features of these rearrangements, we cloned and mapped a 64-kb genomic region containing PAX7 exons 5 through 8. With the use of Southern blot methodology, rearrangements of the 30-kb PAX7 intron 7 were detected in 9 of 9 PAX7-FKHR-positive cases. Similar to our t(2;13) studies, the t(1;13) breakpoints were randomly distributed within the seventh intron. In contrast with the > 90% frequency of reciprocal rearrangements in the t(2;13), reciprocal rearrangements involving the 3' PAX7 region were detected in only 4 of 9 cases. Furthermore, we detected PAX7-FKHR genomic amplification in 10 of 11 cases, in contrast with the < 5% frequency of PAX3-FKHR amplification. The differences in occurrence, reciprocity, and amplification between the PAX3-FKHR and PAX7-FKHR fusions indicate important differences in the mechanism of the two associated chromosomal translocation events.

Child↗
PubMed1997

The winged-helix transcription factor Trident is expressed in actively dividing lymphocytes.

We recently identified the winged-helix transcription factor Trident and described its expression pattern in synchronized fibroblasts. We have now studied Trident expression in cell lines, differentiating thymocytes and in lymphocytes derived from peripheral blood. During T cell differentiation, expression peaked in the actively dividing immature single positive cells. In peripheral blood lymphocytes, expression of Trident mRNA was absent, but could be induced upon stimulation with mitogens in vitro. These observations imply a function for Trident in dividing lymphocytes.

Cell Cycle↗
PubMed2001

Regulating the neoplastic phenotype using engineered transcriptional repressors.

We have applied engineered transcriptional repressors to specifically inhibit disease gene-activated pathways in oncogenesis. We have demonstrated that synthetic repressors combining PAX3 DNA binding domains with different repression domains, KRAB or SNAG, are able to specifically inhibit malignant growth and suppress tumorigenesis in alveolar rhabdomyosarcoma tumor cells transformed by the translocation-derived chimeric transcriptional activator, PAX3-FKHR. We discuss the potential applications of the engineered repressor strategy that relate to target gene analysis, mechanisms of repression, cell regulation, and possible anti-viral and cancer therapy.

Animals↗
PubMed1998

Uncoupling of S phase and mitosis in cardiomyocytes and hepatocytes lacking the winged-helix transcription factor Trident.

In order to maintain a stable karyotype, the eukaryotic cell cycle is coordinated such that only one round of S phase precedes each mitosis, and mitosis is not initiated until DNA replication is completed. Several checkpoints and regulatory proteins have been defined in lower eukaryotes that govern this coordination, but little is known about the proteins that are involved in mammalian cells. Previously, we have shown that the winged-helix transcription factor Trident - also known as HFH-11, FKL16 and WIN [1] [2] [3] - is exclusively expressed in cycling cells and is phosphorylated during mitosis [1] [4]. The cellular function of Trident has yet to be described, however. Here, we have shown that disruption of the Trident gene in mice resulted in postnatal death, most probably because of circulatory failure. Histological analysis of Trident -/- embryos from embryonic day 10 (E10) onwards revealed a specific, characteristic defect in the developing myocardium. The orientation of the myocytes was highly irregular and the nuclei of these disorganized cardiomyocytes were clearly polyploid with up to a 50-fold increase in DNA content. Polyploidy was also observed in embryonic hepatocytes. Our results indicate that expression of Trident is required to prevent multiple rounds of S phase in the heart and the liver. Trident therefore appears to have a role in preventing DNA re-replication during the G2 and M phases.

Animals↗
PubMed2004

The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.

Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the molecular mediators of atrophy and hypertrophy had been reported. We demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. Our study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.

Animals↗
PubMed2004

FoxO: linking new signaling pathways.

Two recent reports reveal new roles for FoxO proteins in cell proliferation and tumorigenesis. Seoane and colleagues show that FoxO proteins play key roles in the TGFbeta-dependent activation of p21Cip1 by partnering with Smad3 and Smad4. FoxG1, a protein from a distinct Fox subfamily, binds FoxO/Smad complexes and blocks p21Cip1 expression. These interactions establish a relationship between the PI3K pathway, FoxG1, and the TGFbeta/Smad pathways. The second report identifies IkappaB kinase as a negative regulator of FoxO proteins, suggesting a mechanism for relieving negative regulation of cell cycle and promoting tumor cell proliferation.

Animals↗
PubMed2003

Restoring functions of tumor suppressors with small molecules.

Developing small molecule inhibitors of oncoproteins, which are activated in tumor cells, is a newly popular strategy for cancer-related drug discovery. The complementary strategy, developing small molecules that restore the function of missing tumor suppressors, is much more difficult to realize. However, in this issue of Cancer Cell, Kau et al. report the discovery of small molecules that reverse some cellular consequences of the loss of the tumor suppressor PTEN.

Active Transport, Cell Nucleus↗
PubMed1998

Sequence specific collective motions in a winged helix DNA binding domain detected by 15N relaxation NMR.

The recognition between transcription factors and their DNA binding sites is a highly dynamic process. During transcriptional regulation, transcription factors must bind to or dissociate from their cognate DNA binding sites. The winged helix DNA binding motif is one of many highly conserved DNA binding motifs identified in transcription factors. Backbone dynamics has been studied on the 15N- and 2H-enriched winged helix family member Genesis. Our data show that the overall motions of the single domain Genesis are better described by more than two autocorrelation times (taum). Our data also demonstrate that Genesis shows structure specific conformation exchange characterized by Rex. Therefore, our results indicate that the structure of Genesis is highly dynamic and that secondary structure elements in Genesis have collective motions in the nanosecond to millisecond time scale. Since the winged helix DNA binding motif is highly conserved, this unique dynamic property observed in Genesis is also likely to be conserved in other winged helix family members and important in DNA binding.

Animals↗
PubMed2005

The psammaplysenes, specific inhibitors of FOXO1a nuclear export.

A small collection of marine natural product extracts was screened for compounds that would compensate lost tumor suppressor functionality in PTEN-deficient cells. From the most active extract, the previously unreported bromotyrosine derivative, psammaplysene A (1), was identified. Psammaplysene A compensates for PTEN loss by relocalizing the transcription factor FOXO1a to the nucleus.

Active Transport, Cell Nucleus↗