A5070809614- Melanoma and MAPK Pathways
- DNA Repair Mechanisms
- Ubiquitin and proteasome pathways
- Endoplasmic Reticulum Stress and Disease
- Drug Transport and Resistance Mechanisms
- Immunotherapy and Immune Responses
- Ferroptosis and cancer prognosis
- Computational Drug Discovery Methods
- Protein Tyrosine Phosphatases
- Carcinogens and Genotoxicity Assessment
- Microtubule and mitosis dynamics
- interferon and immune responses
- Cancer, Lipids, and Metabolism
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Cancer Immunotherapy and Biomarkers
- Calcium signaling and nucleotide metabolism
- Genomics and Chromatin Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Retinoids in leukemia and cellular processes
- Synthesis and biological activity
Albert Einstein College of Medicine
2016-2022
New York University
2010-2012
Deubiquitinating enzymes (DUBs) constitute a large family of cysteine proteases that have broad impact on numerous biological and pathological processes, including the regulation genomic stability. DUBs are often assembled onto multiprotein complexes to assist in their localization substrate selection, yet it remains unclear how enzymatic activity is modulated by intracellular signals. Herein, we show bursts reactive oxygen species (ROS) reversibly inactivate through oxidation catalytic...
Abstract BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic V600E signals as an active monomer absence RAS, however, tumors dimers mediate signaling. FDA-approved RAF inhibitors poorly inhibit dimers, which leads to tumor resistance. We found that Ponatinib, drug, effective inhibitor monomers and dimers. Ponatinib binds dimer stabilizes distinct αC-helix conformation through interaction with previously unrevealed allosteric site. Using...
Targeted protein destruction of critical cellular regulators during the G1 phase cell cycle is achieved by anaphase-promoting complex/cyclosomeCdh1 (APC/CCdh1), a multisubunit E3 ubiquitin ligase. Cells lacking Cdh1 have been shown to accumulate deoxyribonucleic acid (DNA) damage, suggesting that it may play previously unrecognized role in maintaining genomic stability. The ubiquitin-specific protease 1 (USP1) known regulator DNA repair and In this paper, we report USP1 was degraded via...
Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline experimental genetic models has proven beneficial. Here, we have identified mechanism of action selective chaperone-mediated activators previously developed by our group leveraged that information to generate orally bioavailable favorable brain exposure. activating molecules stabilize interaction between retinoic acid receptor alpha - a known...
Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis global cytosine methylation in cohort primary melanomas revealed pattern early demethylation associated with overexpression oncogenic transcripts. Loss the CSF 1 receptor (CSF1R) was seen majority tumors driven an alternative, endogenous viral promoter subset samples. CSF1R particularly elevated BRAF other MAPK activating mutations. Furthermore,...
Abstract Epigenetic changes in cancer are thought to contribute the regulation of invasion and metastasis. To study this at a genome-wide level melanoma, we analyzed methylome 44 cases malignant melanoma. We saw widespread demethylation occurring preferentially outside CpG islands. Comparison primary metastatic lesions showed occurs early during carcinogenesis with few additional alterations advanced tumors. The colony stimulating factor-1 receptor was aberrantly expressed hypomethylated...
Abstract BRAF mutants are present in ~50% of melanoma patients as well colorectal (~10%), thyroid carcinomas (~40%) and other malignancies. FDA-approved RAF inhibitors Vemurafenib, Dabrafenib Encorafenib show remarkable responses with BRAFV600E tumors. However, these drugs ultimately become ineffective due to adaptive acquired resistance mechanisms, many which depend on signaling by poorly inhibited homo- or hetero-dimers. In about 20-30% tumors, intrinsic is driven a constitutive dimer...