E2F-2 is a Retinoblastoma (Rb)-regulated transcription factor induced during terminal erythroid maturation. Cyclin E-mediated Rb hyper-phosphorylation induces E2F transcriptional activator functions. E2F-2-loss causes reduced peripheral red blood cell (RBC) counts, without altering relative abundances of erythroblast subpopulations. To determine how E2F-2 regulates RBC production, we comprehensively studied erythropoiesis using knockout...
Gene expression is tightly regulated at the level of transcription through cooperation between cis-regulatory elements and trans-factors that bind to the regulatory elements. Together, these factors regulate the higher order chromatin structure which establishes domains that organize the genome and coordinate gene expression. However, the molecular mechanisms controlling transcription of...
CD1 molecules represent a class of antigen presenting molecules that present lipid antigens to cognate T cells. These molecules have been identified in all mammals examined so far. Unlike MHC molecules, which are highly polymorphic, CD1 molecules exhibit limited polymorphism and are divided in to two groups – 1 and...
The airway epithelium forms an active barrier between the internal and external environments and has multiple roles critical to normal function of the lung. Its development and function are controlled by a network of transcription factors that regulate gene expression in response to varying stimuli. Dysfunction of this tissue plays...
Kainate receptors (KARs) are expressed throughout the central and peripheral nervous systems. One of three subfamilies of ionotropic glutamate receptors, KARs are localized both pre- and post-synaptically and exert important modulatory control over neural circuits. This modulatory role in circuit function makes them a potential actor in wide variety of...
Radiation is a ubiquitous health risk. Contemporary populations are exposed to several hundred milliSieverts per person over their lifetimes from both natural and human made sources such as radon, cosmic rays, CT-scans, etc. Risk estimates based on studies of atomic bomb survivors suggest that these exposures induce excess cancer mortality...
The polypeptide hormone prolactin (PRL) is increasingly recognized as contributing to the development and progression of human breast cancer. This is supported by epidemiologic studies that found women with high levels of serum PRL are at an increased risk for developing breast cancer. Activation of the prolactin receptor (PRLR) by...
FOXA1 is a FKHD family protein that plays pioneering roles in lineage-specific enhancer activation and gene transcription. Through genome-wide location analyses, here we show that FOXA1 expression and occupancy are, in turn, required for the maintenance of these epigenetic signatures, namely DNA hypomethylation and histone 3 lysine 4 methylation. Mechanistically,...
The African trypanosome Trypanosoma brucei is a single-celled eukaryotic protozoan parasite with a single cilium/flagellum. It cycles between its mammalian host (bloodstream cell), in which it scavenges cholesterol, and its tsetse fly host (procyclic cell), in which it both scavenges cholesterol and synthesizes ergosterol. For the first part of the...
SIRT3 is a mitochondrial-localized, NAD+-dependent deacetylase, tumor suppressor protein that functions to direct mitochondrial energy sensing and antioxidant proteins, increasing the efficiency of energy utilization, providing a redox balanced environment, and preventing aging-related diseases. One SIRT3 deacetylation target is NADP+-dependent isocitrate dehydrogenase 2 (IDH2), a key Krebs Cycle enzyme that...
The hormone prolactin (PRL) contributes to breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the transcription factor STAT5 results in the upregulation of numerous genes implicated in breast cancer pathogenesis. However, the...
Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection gonorrhea and is adapted to survive in humans, its only host. The N. gonorrhoeae cell wall is critical for maintaining envelope integrity, resisting immune cell killing, and production of cytotoxic peptidoglycan (PG) fragments. Deletion of the N. gonorrhoeae genes...
Metabolic abnormalities of cancers provide opportunities for novel tumor-specific therapies. Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG) and the reduction of NAD(P)+ to NAD(P)H. Oncogenic mutations in two IDH-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma...
A number of nonclassical MHC Ib molecules recognizing distinct microbial antigens have been implicated in the immune response to Mycobacterium tuberculosis (Mtb). Due to the low polymorphism of MHC Ib molecules within the human population, these molecules and Mtb antigens are attractive targets for better vaccine development. Among these, HLA-E...
Efferocytosis is the anti-inflammatory removal of dying cells and cellular debris, occurring billions of times per person, per day as a part of homeostatic maintenance during natural cell turnover. Macrophages are major professional phagocytes of the immune system and are responsible for dead cell clearance during infection and injury. During...
Spindle formation in mammalian cells requires precise spatial and temporal regulation of the kinesin-5 motor proteins which generate outward force to establish spindle bipolarity. A growing body of work suggests that phosphorylation of kinesin-5 motor domains is an important regulator of their motor characteristics and function in cells. My thesis...
The development of targeted therapies has revolutionized cancer treatment and markedly increased patient survival time and reduced mortality rates. Yet, some cancers still have few treatment options and remain deadly. In these cases, the development of targeted therapy is critical. Here, we investigated two cancers that lack effective targeted therapies...
Allergic diseases, including asthma, atopic dermatitis, and food allergy, are a widespread health issue. The prevalence of these diseases has been increasing, but the mechanism behind this increase and how allergies develop is not well understood. Although the immune system is central to the pathology of allergy, recent work has...
Tumor progression depends on both tumor-intrinsic processes and interactions with different cell types within tumor microenvironment. Identifying targets that have dual effects on both tumor cells and their interacting surrounding cells, such as tumor-infiltrating immune cells, represent a novel therapeutic approach to treat cancer patients
CD44 is a ubiquitously expressed...
MAPK-interacting kinase (MNK) signaling leads to activation of cap-dependent mRNA translation through phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E). In cancer cells, MNK-eIF4E signaling promotes translation of oncogenic mRNAs. In glioblastoma (GBM), the deadliest malignant brain tumor, MNK-eIF4E signaling is aberrantly activated and represents a promising therapeutic target....