Biomedical subjects

Brooke M Emerling

Publications and source records attributed to Brooke M Emerling.

6 recordsLinked to original sources

PubMed2005

Oxygen sensing: getting pumped by sterols.

Oxygen plays a pivotal role in the maintenance of life for all eukaryotes, with the exception of strict anaerobes. Eukaryotes have developed mechanisms to sense and respond to decreased oxygen levels. How eukaryotes sense oxygen is still not fully understood. What is (or are) the oxygen sensor(s)? This question has vital physiological and pathophysiological implications, because all living aerobic organisms have adaptive mechanisms to maintain oxygen homeostasis. A recent report describes a novel eukaryotic oxygen-sensing mechanism in the fission yeast Schizosaccharomyces pombe, involving the depletion of sterols as a trigger to induce gene expression in response to decreased oxygen levels. It is not yet clear whether this mechanism is involved in the mammalian response to hypoxia, possibly in conjunction with activation of one or both of the hypoxia-inducible factor (HIF-1 or HIF-2) transcription factors.

Aerobiosis↗

PubMed2005

Mitochondrial regulation of oxygen sensing.

Maintenance of oxygen homoeostasis is required for the survival of higher organisms. The transcription factor hypoxia inducible factor (HIF) has a crucial role in oxygen homoeostasis by integrating the decrease in oxygen levels to increase hypoxic gene expression. How cells sense decrease in oxygen levels to elicit an increase in HIF dependent gene expression is not fully understood. In this review, we discuss the role of mitochondria as oxygen sensors regulating HIF.

Animals↗

PubMed2005

Isolation and analysis of candidate myeloid tumor suppressor genes from a commonly deleted segment of 7q22.

Monosomy 7 and deletions of 7q are recurring leukemia-associated cytogenetic abnormalities that correlate with adverse outcomes in children and adults. We describe a 2.52-Mb genomic DNA contig that spans a commonly deleted segment of chromosome band 7q22 identified in myeloid malignancies. This interval currently includes 14 genes, 19 predicted genes, and 5 predicted pseudogenes. We have extensively characterized the FBXL13, NAPE-PLD, and SVH genes as candidate myeloid tumor suppressors. FBXL13 encodes a novel F-box protein, SVHis a member of a gene family that contains Armadillo-like repeats, and NAPE-PLD encodes a phospholipase D-type phosphodiesterase. Analysis of a panel of leukemia specimens with monosomy 7 did not reveal mutations in these or in the candidate genes LRRC17, PRO1598, and SRPK2. This fully sequenced and annotated contig provides a resource for candidate myeloid tumor suppressor gene discovery.

Base Sequence↗

PubMed2005

Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling.

Mammalian cells have the ability to sense low oxygen levels (hypoxia). An adaptive response to hypoxia involves the induction of the transcription factor hypoxia-inducible factor 1 (HIF-1). The intracellular signaling pathways that regulate HIF-1 activation during hypoxia remain unknown. Here, we demonstrate that p38alpha-/- cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38alpha, also fail to activate HIF-1 under hypoxic conditions. The p38alpha-/- cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38alpha and HIF-1 was abolished by myxothiazol, a mitochondrial complex III inhibitor, and glutathione peroxidase 1 (GPX1), a scavenger of hydrogen peroxide. Thus, the activation of p38alpha and HIF-1 is dependent on the generation of mitochondrial reactive oxygen species. These results provide genetic evidence that p38 mitogen-activated protein kinase signaling is essential for HIF-1 activation.

Animals↗

PubMed2002

MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia.

Proteins encoded by Polycomb and Trithorax-group (Pc-G and Trx-G) genes regulate developmental fates by maintaining or repressing HOX gene expression, respectively. In a search for candidate myeloid leukemia tumor suppressor genes from a approximately 2.5 Mb commonly-deleted segment within chromosome band 7q22, we identified a novel human Trithorax (Trx) family member named MLL5. Trx-G genes encode proteins that modulate transcriptional programs through protein-protein interactions that are mediated by PHD and SET domains, and by binding to DNA via A-T hooks and methyltransferase homology motifs. MLL5 is a homolog of the Drosophila gene CG9007; it encodes a 6.5 kb mRNA that is expressed widely. MLL5 includes a SET domain and a single PHD finger, but lacks A-T hooks and methyltransferase homology domains that are found in MLL. The leukemia cell line RCV-ACV-A carries a heterozygous missense mutation within the PHD domain; however, no mutations within the MLL5 coding region were detected in primary leukemias. MLL5 is a novel mammalian Trx-G gene that might modulate transcription by protein association.

Amino Acid Sequence↗

PubMed2002

Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor.

PIK3CG, which encodes the catalytic subunit p110 gamma of phosphoinositide 3-OH-kinase-gamma (PI3K gamma), has been assigned to chromosome band 7q22, a region that is frequently deleted in myeloid malignancies. PI3K gamma-mutant mice have hematologic defects and are predisposed to colon cancer. On the basis of these data, PIK3CG was evaluated as a candidate myeloid tumor suppressor gene (TSG). PIK3CG was mapped by fluorescence in situ hybridization adjacent and telomeric to a commonly deleted segment defined previously in myeloid leukemias with breakpoints within 7q22. PIK3CG contains 10 exons and spans approximately 37 kilobases of genomic DNA. Forty leukemias with monosomy 7 or a del(7q) were screened for PIK3CG mutations. Two patients had missense variations affecting residue 859 in the N-terminal catalytic domain of the protein. This allele was also detected in unaffected parents and in 1 of 60 control alleles; it probably represents a polymorphism. PIK3CG is unlikely to act as a recessive TSG in myeloid leukemias with monosomy 7.

Chromosome Mapping↗