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Charles Lee

Publications and source records attributed to Charles Lee.

52 records · Page 3Linked to original sources
PubMed2004

Germ cell aneuploidy in zebrafish with mutations in the mitotic checkpoint gene mps1.

Aneuploidy, resulting from chromosome missegregation during meiosis, is a major cause of human infertility and birth defects. However, its molecular basis remains incompletely understood. Here we have identified a spectrum of chromosome anomalies in embryos of zebrafish homozygous for a hypomorphic mutation in Mps1, a kinase required for the mitotic checkpoint. These aneuploidies are caused by meiotic error and result in severe developmental defects. Our results reveal Mps1 as a critical regulator of chromosome number in zebrafish, and demonstrate how slight genetic perturbation of a mitotic checkpoint factor can dramatically reduce the fidelity of chromosome segregation during vertebrate meiosis.

Aneuploidy↗
PubMed2004

Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells.

The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (IgH)/c-myc coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and c-myc amplification and instead coamplified IgH and N-myc through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target IgH locus translocations to particular oncogenes.

Animals↗
PubMed2004

An allograft model of androgen independent prostatic neuroendocrine carcinoma derived from a large probasin promoter-T antigen transgenic mouse line.

PURPOSE: Animal models that mimic this hormone refractory prostate cancer may be useful for developing and testing novel treatment strategies. MATERIALS AND METHODS: Using the prostate of the 12T-10 transgenic mouse an allograft model was established by transplantation into a nude mouse. To our knowledge we describe the first allograft model derived from the primary prostate tumor of a transgenic mouse. RESULTS: The primary tumor progressed from high grade prostatic intraepithelial neoplasm to invasive, undifferentiated and metastatic cancer with loss of androgen receptor expression. After 10 passages in nude mice the allograft retained the same histological and immunohistochemical features as the primary tumors, including neuroendocrine differentiation. The allograft demonstrated androgen independent growth and metastases to liver and lung, paralleling tumor behavior in the original transgenic line. Cytogenetic characterization of the allograft revealed consistent chromosomal abnormalities for multiple in vivo passages. CONCLUSIONS: This allograft model may give insight into the mechanism by which human prostate cancer progresses to an androgen independent state and provide a system for testing drugs that can inhibit this disease.

Androgen-Binding Protein↗
PubMed2003

Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors.

We employed gene targeting to study H2AX, a histone variant phosphorylated in chromatin surrounding DNA double-strand breaks. Mice deficient for both H2AX and p53 (H(delta/delta)P(-/-)) rapidly developed immature T and B lymphomas and solid tumors. Moreover, H2AX haploinsufficiency caused genomic instability in normal cells and, on a p53-deficient background, early onset of various tumors including more mature B lymphomas. Most H2AX(delta/delta)p53(-/-) or H2AX(+/delta)p53(-/-) B lineage lymphomas harbored chromosome 12 (IgH)/15 (c-myc) translocations with hallmarks of either aberrant V(D)J or class switch recombination. In contrast, H2AX(delta/delta)p53(-/-) thymic lymphomas had clonal translocations that did not involve antigen receptor loci and which likely occurred during cellular expansion. Thus, H2AX helps prevent aberrant repair of both programmed and general DNA breakage and, thereby, functions as a dosage-dependent suppressor of genomic instability and tumors in mice. Notably, H2AX maps to a cytogenetic region frequently altered in human cancers, possibly implicating similar functions in man.

Animals↗
PubMed2003

Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib.

Eosinophilia is common in myeloproliferative disorders (MPDs) with abnormalities of chromosome band 5q31-33, including those that present with t(1;5)(q23;q33). With the development of rational drug therapy, characterization of the molecular targets for these translocations could guide treatment and affect patient survival. We cloned the t(1;5)(q23;q33) and showed that it fuses platelet-derived growth factor receptor beta (PDGFRB) to the coiled-coil domains of a novel partner protein, myomegalin. Using two-color interphase fluorescence in situ hybridization (FISH), we also demonstrated that the eosinophils are clonal in these disorders. Imatinib mesylate has recently been shown to be efficacious in MPDs with PDGFR activation. Therefore, following our molecular studies, we were able to redirect this patient's treatment. Although she had refractory and progressive disease, once imatinib was started, complete clinical and hematologic remission, as well as major cytogenetic response, was achieved. Given the therapeutic implications, our findings stress the need to aggressively investigate the molecular basis of these diseases, with emphasis on the PDGFR family.

Benzamides↗
PubMed2003

A p53-dependent checkpoint pathway prevents rereplication.

Eukaryotic cells control the initiation of DNA replication so that origins that have fired once in S phase do not fire a second time within the same cell cycle. Failure to exert this control leads to genetic instability. Here we investigate how rereplication is prevented in normal mammalian cells and how these mechanisms might be overcome during tumor progression. Overexpression of the replication initiation factors Cdt1 and Cdc6 along with cyclin A-cdk2 promotes rereplication in human cancer cells with inactive p53 but not in cells with functional p53. A subset of origins distributed throughout the genome refire within 2-4 hr of the first cycle of replication. Induction of rereplication activates p53 through the ATM/ATR/Chk2 DNA damage checkpoint pathways. p53 inhibits rereplication through the induction of the cdk2 inhibitor p21. Therefore, a p53-dependent checkpoint pathway is activated to suppress rereplication and promote genetic stability.

Animals↗
PubMed2003

Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency.

Most eukaryotic cell types use a common program to regulate the process of cell division. During mitosis, successful partitioning of the genetic material depends on spatially coordinated chromosome movement and cell cleavage. Here we characterize a zebrafish mutant, retsina (ret), that exhibits an erythroid-specific defect in cell division with marked dyserythropoiesis similar to human congenital dyserythropoietic anemia. Erythroblasts from ret fish show binuclearity and undergo apoptosis due to a failure in the completion of chromosome segregation and cytokinesis. Through positional cloning, we show that the ret mutation is in a gene (slc4a1) encoding the anion exchanger 1 (also called band 3 and AE1), an erythroid-specific cytoskeletal protein. We further show an association between deficiency in Slc4a1 and mitotic defects in the mouse. Rescue experiments in ret zebrafish embryos expressing transgenic slc4a1 with a variety of mutations show that the requirement for band 3 in normal erythroid mitosis is mediated through its protein 4.1R-binding domains. Our report establishes an evolutionarily conserved role for band 3 in erythroid-specific cell division and illustrates the concept of cell-specific adaptation for mitosis.

Amino Acid Sequence↗
PubMed2003

Atypical presentation and progression of glioblastoma multiforme in a 6-year-old girl: multidisciplinary case report.

Glioblastoma multiforme is the most common adult malignant brain tumor but is notably less common in children. The authors describe the case of a child who presented for evaluation and treatment of neurologic signs caused by a brain stem glioma. Response to radiotherapy and chemotherapy with temozolomide was initially positive, but later extensive leptomeningeal metastasis developed. Biopsy proved the lesion to be glioblastoma multiforme. During salvage irradiation to the spine and unirradiated brain, the patient complained of hip and femur pain. Subsequent radiographs demonstrated multiple bony metastases. This pattern of spread is uncharacteristic and emphasizes the importance of adequate metastatic evaluation.

Bone Neoplasms↗
PubMed2002

Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.

Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAG1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation.

Animals↗
PubMed2002

Intracranial subdural hematoma following dural puncture in a parturient with HELLP syndrome.

PURPOSE: To present a case of postpartum bilateral intracranial subdural hematoma after dural puncture during attempted epidural analgesia for labour. CLINICAL FEATURES: This complication occurred following accidental dural puncture in a parturient with thrombocytopenia (99,000 x microL-1) who subsequently developed the syndrome of hemolysis, elevated liver enzymes and low platelets. On the first postoperative day, postdural puncture headache (PDPH) developed. An epidural blood patch (EBP) was deferred to the third postoperative day because of a platelet count of 21,000 x micro L-1. However, the headache intensified from a typical PDPH to one which was not posturally related. A second EBP was abandoned after the injection of 5 mL of blood because of increasing headache during the procedure. Magnetic resonance imaging revealed bilateral temporal subdural hematomas. The patient was managed conservatively and discharged home without any sequelae. CONCLUSION: It is conceivable that thrombocytopenia together with possible abnormal platelet function increased the risk of subdural hematoma. Alternative diagnoses to PDPH should be considered whenever headache is not posturally related.

Adult↗
PubMed2002

Environmental justice: building a unified vision of health and the environment.

The assorted and multidimensional concerns that give rise to the issue of environmental justice have proved to be intellectually daunting and highly resistant to positive change. Low-income, people of color, and tribal communities confronting environmental stressors are beset by stressors in both the physical and social environments. For this reason, while the bifurcation of the public health and environmental fields taking place over the past several decades has yielded generally negative impacts in areas of public health, environment, and planning, the consequences for low-income and disadvantaged communities have been especially grievous. This commentary builds on the recent Institute of Medicine workshop titled "Rebuilding the Unity of Health and the Environment: A New Vision of Environmental Health for the 21st Century." The workshop organizers posited that only by thinking about environmental health on multiple levels will it be possible to merge various strategies to protect both the environment and health. In this commentary we examine how such a new vision of uniting public health and the environment can contribute to attaining environmental justice for all populations.

Environmental Health↗