A5061092393- Protein Degradation and Inhibitors
- Acute Myeloid Leukemia Research
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Cell Adhesion Molecules Research
- Cell death mechanisms and regulation
- Cancer-related Molecular Pathways
- Cancer, Lipids, and Metabolism
- Multiple Myeloma Research and Treatments
- Angiogenesis and VEGF in Cancer
- MicroRNA in disease regulation
- Immune cells in cancer
- Nuclear Structure and Function
- Immune Response and Inflammation
- NF-κB Signaling Pathways
- Chronic Lymphocytic Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Circular RNAs in diseases
- T-cell and B-cell Immunology
- RNA Interference and Gene Delivery
- Protein Kinase Regulation and GTPase Signaling
- Protease and Inhibitor Mechanisms
- Hippo pathway signaling and YAP/TAZ
Vanderbilt University
2003-2024
Vanderbilt University Medical Center
2013-2023
Yale University
2020
Bipar
2014-2015
University of Massachusetts Chan Medical School
2010
Grace (United States)
1999
University of Alabama at Birmingham
1992-1995
Institute of Molecular Biology and Biophysics
1995
University of Alabama
1995
Pontificia Universidad Católica de Valparaíso
1993
Suppression of apoptosis by expression antiapoptotic BCL2 family members is a hallmark acute myeloblastic leukemia (AML). Induced myeloid cell differentiation protein (MCL1), an member, commonly upregulated in AML cells and often primary mode resistance to treatment with the inhibitor venetoclax. Here, we describe VU661013, novel, potent, selective MCL1 that destabilizes BIM/MCL1 association, leads AML, active venetoclax-resistant patient-derived xenografts. In addition, VU661013 was safely...
We have identified a third member of the junctional adhesion molecule (JAM) family. At protein level JAM3 displays 36 and 32% identity to JAM2 JAM1, respectively. The coding region is distributed over 9 exons maps chromosome 11q25. gene shows widespread tissue expression with higher levels apparent in kidney, brain, placenta. cellular we show transcript within endothelial cells. Our major finding that are binding partners. Thus, ectodomain binds firmly JAM2-Fc. This heterotypic interaction...
We have isolated and cloned a novel epithelial Cl− channel protein from bovine tracheal cDNA expression library using an antibody probe. The (αp38) was raised against 38-kDa component of homopolymeric that behaves as Ca2+/calmodulin kinase II-, DIDS-, dithiothreitol (DTT)-sensitive, anion-selective when incorporated into planar lipid bilayers. full-length is 3001 base pairs long codes for 903-amino acid protein. clone does not show any significant homology to other previously reported...
MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution lung tumorigenesis. Here, we determined that miR-31 overexpressed in human adenocarcinoma this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model allows for lung-specific test the oncogenic potential lung. Using model, observed induction results hyperplasia,...
We have previously reported that junctional adhesion molecule 2 (JAM2) adheres to T cells through heterotypic interactions with JAM3. An examination of the cation dependence JAM2 HSB revealed a Mn2+-enhanced binding component indicative integrin involvement. Using neutralizing antibodies, we defined an interaction between and α4β1 in cells. The is readily amenable drug intervention as demonstrated by ability TBC 772, α4-specific inhibitor, attenuate component. Intriguingly, engagement only...
We have cloned a novel cDNA belonging to the Ig superfamily that shows 44% similarity junctional adhesion molecule (JAM) and maps chromosome 21q21.2. The open reading frame of JAM2 predicts 34-kDa type I integral membrane protein features two Ig-like folds three <i>N</i>-linked glycosylation sites in extracellular domain. A single kinase C phosphorylation consensus site PDZ-binding motif are present short intracellular tail. Heterologous expression Chinese hamster ovary cells defined 48-kDa...
Abstract The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the major tumor suppressor proteins growth regulators such as p53, p21, p27. XPO1 also affects translation messenger RNAs critical oncogenes, including MYC, BCL2, MCL1, BCL6, by blocking initiation factor eIF4E. Early trials with venetoclax...
Abstract Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical dampened enthusiasm for BETi as a single agent. resistance AML myeloblasts was found to correlate maintaining mitochondrial respiration, suggesting that identifying metabolic pathway sustaining integrity could help develop approaches improve efficacy. Herein, we...
We have examined the interactions of p85 regulatory subunit phosphatidylinositol 3-kinase with endothelium-specific Flt-1 receptor tyrosine kinase using yeast two-hybrid system. find that both amino- and carboxyl-terminal SH2 domains bind to Flt-1. performed site-directed mutagenesis on tail in order identify site(s) is responsible for interactions. A single phenylalanine change at position 1213 inhibits binding domains. Phosphopeptide mapping wild type mutant protein expressed insect cells...
Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) used combination with azacitidine (AZA), DNAmethyltransferase inhibitor (DNMTi), to treat patients AML. Despite promising response rates VEN/AZA, resistance the agent common. One identified upregulation cell leukemia-1 protein...
Abstract We characterized the electrophysiological properties of a chloride channel protein isolated from bovine trachea after incorporation into planar lipid bilayers, and studied effects thiol-modulating agents on regulation both in bilayers vesicular iodide uptake studies. Our experiments showed that this formed perfectly anion-selective channels bilayer, with an anion permeability sequence I- (2.1) > NO3- (1.7) Br- (1.2) Cl- (1.0). The conductance was 25-30 picosiemens 150 mM Cl-,...
Reoviruses induce apoptosis both in cultured cells and vivo. Apoptosis plays a major role the pathogenesis of reovirus encephalitis myocarditis infected mice. Reovirus-induced is dependent on activation transcription factor NF-kappaB downstream cellular genes. To better understand mechanism by reovirus, signaling intermediates under control were investigated at level Rel, IkappaB, IkappaB kinase (IKK) proteins. We found that infection leads initially to nuclear translocation p50 RelA,...
Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant contributes to their tumorigenic phenotype. In support this, Dicer, an RNase III-like enzyme controls the maturation miRNA, was recently shown function as a haploinsufficient suppressor nonhematopoietic cells. Because Myc oncoprotein, critical inducer B-cell lymphomas, reported suppress multiple miRNAs lymphoma cells, it presumed deficiency Dicer and subsequent...
Despite its involvement in most human cancers, MYC continues to pose a challenge as readily tractable therapeutic target. Here we identify the transcriptional cofactors TIP48 and TIP49 novel binding partners of Mdm2-binding protein (MTBP), functionally undefined that show is oncogenic overexpressed many cancers. MTBP associated with at promoters increased MYC-mediated transcription, proliferation, neoplastic transformation, tumor development. In breast cancer specimens, determined...
A bovine homologue of the rat and human epithelial Na+ channel subunits, alpha-rENaC alpha-hENaC, was cloned. The cDNA clone, termed alpha-bENaC, isolated from a renal papillary collecting duct expression library. is 3,584 base pairs (bp) long, has an open reading frame 2,094 bp encoding 697-amino acid protein, 75-85% homologous to its counterparts. In vitro translation transcribed cRNA yields 80-kDa polypeptide one at 92 kDa in presence pancreatic microsomes. clone exhibits consensus...
Abstract Transcription factor NF-κB controls the expression of multiple genes involved in immunity and inflammation. The initial activation duration signaling is regulated by posttranslational modifications to IκB kinase, which earmarks inhibitors for degradation. Prior studies suggest that K63-linked ubiquitination NEMO (NF-κB essential modulator), an kinase regulatory subunit, critical MAPK following engagement Ag receptors. We now demonstrate pathways are largely unaffected primary cells...
The kinase insert domain-containing receptor (KDR) tyrosine mediates calcium mobilization in endothelial cells and plays a key role during physiological pathological angiogenesis. To provide detailed understanding of how KDR is activated, we analyzed the kinetics ligand-receptor interaction using BIAcore. Both predimerized (KDR-Fc) monomeric (KDR-cbu) receptors were examined with vascular cell growth factor (VEGF) homodimers VEGF/placental (PlGF) heterodimers. VEGF binds to KDR-Fc ka = 3.6 ±...
Initiation of the genetic programs for inflammation and immunity involves nuclear mobilization transcription factor NF-κB. This signal-dependent process is controlled in part by β-catalytic subunit IκB kinase (IKKβ), which marks IκBα other cytoplasmic inhibitors NF-κB proteolytic destruction. The catalytic activity IKKβ stimulated pathologic physiologic inducers NF-κB, such as Tax oncoprotein proinflammatory cytokines. We now report evidence that these target conjugation to ubiquitin (Ub)...
Abstract Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators critical AML oncogenes. We tested the efficacy novel BET inhibitor INCB054329, its synergy with venetoclax reduce without...
We have prepared a polyclonal mouse antibody directed against the first three immunoglobulin-like domains of kinase insert domain-containing receptor (KDR) tyrosine kinase. It possesses ability to inhibit binding 165-amino acid splice variant vascular endothelial cell growth factor (VEGF165) recombinant KDR in vitro as well reduce VEGF165 human umbilical vein cells (HUVEC). These results confirm that are involved interactions. The anti-KDR is able completely block VEGF165-mediated...
Transcription factor NF-kappaB governs the expression of multiple genes involved in cell growth, immunity, and inflammation. Nuclear translocation is regulated from cytoplasm by IkappaB kinase-beta (IKKbeta), which earmarks inhibitors for polyubiquination proteasome-mediated degradation. Activation IKKbeta contingent upon signal-induced phosphorylation its T loop at Ser-177/Ser-181. also renders a substrate monoubiquitination cells exposed to chronic activating cues, such as Tax oncoprotein...