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1.
Astrobiology ; 23(1): 94-104, 2023 01.
Article in English | MEDLINE | ID: mdl-36450114

ABSTRACT

Several permanently cold solar system bodies are being investigated with regard to their potential habitability, including Mars and icy moons. In such locations, microbial life would have to cope with low temperatures and both high and low pressures, ranging from ∼102 to 103 Pa on the surface of Mars to upward of ∼108-109 Pa in the subsurface oceans of icy moons. The bacterial genus Carnobacterium consists of species that were previously shown to be capable of growth in the absence of oxygen at low temperatures and at either low pressure or high pressure, but to date the entire pressure range of the genus has not been explored. In the present study, we subjected 14 Carnobacterium strains representing 11 species to cultivation in a complex liquid medium under anaerobic conditions at 2°C and at a range of pressures spanning 5 orders of magnitude, from 103 to 107 Pa. Eleven of the 14 strains showed measurable growth rates at all pressures tested, representing the first demonstration of terrestrial life forms capable of growth under such a wide range of pressures. These findings expand the physical boundaries of the capabilities of life to occur in extreme extraterrestrial environments.


Subject(s)
Extraterrestrial Environment , Mars , Carnobacterium , Solar System , Oceans and Seas , Moon , Exobiology
2.
EMBO J ; 36(15): 2233-2250, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28663241

ABSTRACT

O-GlcNAcylation is an essential, nutrient-sensitive post-translational modification, but its biochemical and phenotypic effects remain incompletely understood. To address this question, we investigated the global transcriptional response to perturbations in O-GlcNAcylation. Unexpectedly, many transcriptional effects of O-GlcNAc transferase (OGT) inhibition were due to the activation of NRF2, the master regulator of redox stress tolerance. Moreover, we found that a signature of low OGT activity strongly correlates with NRF2 activation in multiple tumor expression datasets. Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regulator of NRF2, as a direct substrate of OGT We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiquitination and degradation of NRF2. Interestingly, O-GlcNAc levels and NRF2 activation co-vary in response to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstream stress resistance. Our results reveal a novel regulatory connection between nutrient-sensitive glycosylation and NRF2 signaling and provide a blueprint for future approaches to discover functionally important O-GlcNAcylation events on other KLHL family proteins in various experimental and disease contexts.


Subject(s)
Gene Expression Regulation , Glycosylation , Kelch-Like ECH-Associated Protein 1/metabolism , N-Acetylglucosaminyltransferases/metabolism , NF-E2-Related Factor 2/metabolism , Signal Transduction , Stress, Physiological , Cell Line , Food , Gene Expression Profiling , Humans , Oxidation-Reduction
4.
Proc Natl Acad Sci U S A ; 103(44): 16266-71, 2006 Oct 31.
Article in English | MEDLINE | ID: mdl-17056717

ABSTRACT

The targeted inactivation of oncogenes offers a rational therapeutic approach for the treatment of cancer. However, the therapeutic inactivation of a single oncogene has been associated with tumor recurrence. Therefore, it is necessary to develop strategies to override mechanisms of tumor escape from oncogene dependence. We report here that the targeted inactivation of MYC is sufficient to induce sustained regression of hematopoietic tumors in transgenic mice, except in tumors that had lost p53 function. p53 negative tumors were unable to be completely eliminated, as demonstrated by the kinetics of tumor cell elimination revealed by bioluminescence imaging. Histological examination revealed that upon MYC inactivation, the loss of p53 led to a deficiency in thrombospondin-1 (TSP-1) expression, a potent antiangiogenic protein, and the subsequent inability to shut off angiogenesis. Restoration of p53 expression in these tumors re-established TSP-1 expression. This permitted the suppression of angiogenesis and subsequent sustained tumor regression upon MYC inactivation. Similarly, the restoration of TSP-1 alone in p53 negative tumors resulted in the shut down of angiogenesis and led to sustained tumor regression upon MYC inactivation. Hence, the complete regression of tumor mass driven by inactivation of the MYC oncogene requires the p53-dependent induction of TSP-1 and the shut down of angiogenesis. Notably, overexpression of TSP-1 alone did not influence tumor growth. Therefore, the combined inactivation of oncogenes and angiogenesis may be a more clinically effective treatment of cancer. We conclude that angiogenesis is an essential component of oncogene addiction.


Subject(s)
Neoplasms/metabolism , Neoplasms/pathology , Proto-Oncogene Proteins c-myc/metabolism , Thrombospondin 1/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Cell Line, Tumor , Mice , Neoplasms/blood supply , Neoplasms/genetics , Proto-Oncogene Proteins c-myc/genetics , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics
5.
J Biomol Screen ; 8(4): 447-52, 2003 Aug.
Article in English | MEDLINE | ID: mdl-14567797

ABSTRACT

Homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) assays represent a highly sensitive and robust high-throughput screening (HTS) method for the quantification of kinase activity. Traditional TR-FRET kinase assays detect the phosphorylation of an exogenous substrate. The authors describe the development and optimization of a TR-FRET technique that measures the autophosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2) kinase and extend its applicability to a variety of other kinases. The VEGFR-2 assay demonstrated dose-dependent inhibition by compounds known to modulate the catalytic activity of this receptor. In addition, kinetic analysis of a previously characterized VEGFR-2 inhibitor was performed using the method, and results were consistent with those obtained using a different assay format. Because of the known involvement of VEGFR-2 in angiogenesis, this assay should facilitate HTS for antiangiogenic agents. In addition, this general technique should have utility for the screening for inhibitors of kinases as potential therapeutic agents for many other disease indications.


Subject(s)
Enzyme Inhibitors/pharmacology , Fluorescence Resonance Energy Transfer , Phosphotransferases/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Antibodies/chemistry , Antibodies/immunology , Biotinylation , Fluoroimmunoassay/methods , Indoles/pharmacology , Kinetics , Peptides/metabolism , Phosphorylation , Phosphotransferases/antagonists & inhibitors , Pyrroles/pharmacology , Sunitinib , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
6.
J Med Chem ; 46(7): 1116-9, 2003 Mar 27.
Article in English | MEDLINE | ID: mdl-12646019

ABSTRACT

To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Indoles/chemical synthesis , Pyrroles/chemical synthesis , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , 3T3 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Availability , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Indoles/pharmacology , Mice , Pyrroles/chemistry , Pyrroles/pharmacology , Solubility , Structure-Activity Relationship , Sunitinib
7.
Blood ; 101(7): 2797-803, 2003 Apr 01.
Article in English | MEDLINE | ID: mdl-12517816

ABSTRACT

The targeted inactivation of oncogenes may be a specific and effective treatment for cancer. However, because human cancers are the consequence of multiple genetic changes, the inactivation of one oncogene may not be sufficient to cause sustained tumor regression. Moreover, cancers are genomically unstable and may readily compensate for the inactivation of a single oncogene. Here we confirm by spectral karyotypic analysis that MYC-induced hematopoietic tumors are highly genetically complex and genomically unstable. Nevertheless, the inactivation of MYC alone was found to be sufficient to induce sustained tumor regression. After prolonged MYC inactivation, some tumors exhibited a distinct propensity to relapse. When tumors relapsed, they no longer required the overexpression of MYC but instead acquired novel chromosomal translocations. We conclude that even highly genetically complex cancers are reversible on the inactivation of MYC, unless they acquire novel genetic alterations that can sustain a neoplastic phenotype.


Subject(s)
Gene Silencing/drug effects , Genes, myc/drug effects , Lymphoma/genetics , Translocation, Genetic , Animals , Cell Transformation, Neoplastic/genetics , Cytogenetic Analysis , Doxycycline/administration & dosage , Doxycycline/pharmacology , Lymphoma/drug therapy , Lymphoma/etiology , Mice , Recurrence , Treatment Outcome , Tumor Cells, Cultured
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