A5013327462- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Protein Degradation and Inhibitors
- Protein Kinase Regulation and GTPase Signaling
- Immunotherapy and Immune Responses
- Biochemical and Molecular Research
- Viral-associated cancers and disorders
- Cancer-related gene regulation
- Mast cells and histamine
- Lymphatic System and Diseases
- Adrenal Hormones and Disorders
- TGF-β signaling in diseases
- Immunodeficiency and Autoimmune Disorders
- Chronic Myeloid Leukemia Treatments
- Immune Cell Function and Interaction
- Neonatal Respiratory Health Research
Benaroya Research Institute
2023-2024
University of California, Irvine
2016-2021
Institute of Immunology
2014
Significance Rapamycin is an immunosuppressive drug that partially inhibits the cellular kinase mammalian target of rapamycin (mTOR). This study uncovers previously unidentified mechanisms mTOR signaling in B cells. Antigen recognition and other signals activate mTOR, a central driver lymphocyte proliferation differentiation. However, forms two protein complexes (mTORC1 mTORC2) whose roles B-cell differentiation are poorly defined. We found new class ATP-competitive inhibitors (TOR-KIs) can...
During an adaptive immune response, activated mature B cells give rise to Ab-secreting plasma fight infection. undergo Ab class switching produce different classes of Abs with varying effector functions. The mammalian/mechanistic target rapamycin (mTOR) signaling pathway is during this process, and disrupting mTOR complex 1 (mTORC1) in impairs by a poorly understood mechanism. In particular, it unclear which mTORC1 downstream substrates control process. study, we used vitro murine model the...
The class I PI3Ks are important enzymes that relay signals from cell surface receptors to downstream mediators driving cellular functions. Elevated PI3K signaling is found in B malignancies and lymphocytes of patients with autoimmune disease. p110δ catalytic isoform a rational target since it critical for lymphocyte development, survival, activation, differentiation. In addition, activating mutations PIK3CD encoding cause human immunodeficiency known as activated delta syndrome (APDS)....
Abstract Background The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower rate to monotherapy diffuse large B-cell lymphoma (DLBCL). Methods We tested inhibitors of cap-dependent mRNA translation for ability sensitise DLBCL and mantle cell (MCL) cells apoptosis by venetoclax. compared mTOR kinase (TOR-KI) MLN0128 SBI-756, compound targeting...
The cap-binding protein eukaryotic initiation factor 4E (eIF4E) promotes translation of mRNAs associated with proliferation and survival is an attractive target for cancer therapeutics. Here, we used
Abstract The thymus is an important site for the establishment of appropriate immune response through positive and negative selection developing T cells. During selection, cells interact with cortical medullary thymic epithelial (TECs), termed cTECs mTECs, respectively. Using a Foxn1Cre+/-SKIfl/fl mouse model, we found that TEC-specific deletion SKI reduced mTEC compartment in tissue-restricted Ag expression mTECs was altered. This decrease area led to CD4 thymocyte cellularity; however,...
Abstract During an immune response, activated B cells give rise to antibody secreting plasma fight infection. undergo a process known as class switch recombination (CSR) produce different classes of antibodies with varying effector functions. The mammalian target Rapamycin (mTOR) signaling pathway is during this and inhibition mTOR suppresses both proliferation differentiation into cells. kinase that found in two distinct complexes, mTORC1 mTORC2 deficient have impaired survival,...
Abstract The purpose of this project is to investigate the feasibility using small molecules targeting cap-dependent translation sensitize B cell lymphoma cells killing by BCL-2 inhibitors (venetoclax/ ABT-199). We hypothesized that diffuse large B-cell (DLBCL) survival requires translation, which facilitated eukaryotic initiation factor 4E (eIF4E)-eIF4G interaction and promoted mTOR complex 1 (mTORC1). used compound SBI-756, a novel inhibitor scaffolding protein eIF4G (1). SBI-756 more...
Abstract mTORC1 signaling is elevated in most lymphoid malignancies and frequently associated with poor prognosis. Targeting rapalogs or mTOR kinase inhibitors (TOR-KIs) are two strategies that both have limitations. Rapalogs weak inducers of apoptosis, mainly due to incomplete inhibition, resulting reduced phosphorylation some substrates such as S6K1, but not 4E-BP1. TOR-KIs inhibit more completely, also mTORC2, which likely contributes dose-limiting toxicities TOR-KI clinical trials. We...
Abstract The thymus is an important site for the establishment and maintenance of appropriate immune response through positive negative selection developing T cells. Cortical medullary thymic epithelial cells (TECs), termed cTECs mTECs, respectively, interact with thymocytes to mediate this process. Developing also support maturation proliferation mTECs by secreting transforming growth factor-beta (TGF-β) superfamily cytokines. Our lab has previously shown that deletion TGF-β signaling in...