About

414
Publications
23,173
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20,566
Citations
Research Experience
October 2004 - present
Sanford Burnham Prebys Medical Discovery Institute
Position
  • Scientific Director
June 1998 - June 2005
Icahn School of Medicine at Mount Sinai
Position
  • Professor (Full)

Publications

Publications (414)
Article
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Among the hallmarks of melanoma, are impaired proteostasis and the rapid development of resistance to targeted therapy, that represent a major clinical challenge. However, the molecular machinery that links these processes is unknown. Here we describe that by stabilizing key melanoma oncoproteins the ubiquitin ligase RNF4 promotes tumorigenesis and...
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Metastasis is the major cause of death in cancer patients. Recent studies have demonstrated that the crosstalk between different host and tumor cells in the tumor microenvironment regulates tumor progression and metastasis. Specifically, immune cell myeloid skewing is a prominent promoter of metastasis. While previous studies have demonstrated that...
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Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated tra...
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BRUCE/Apollon is a membrane-associated inhibitor of apoptosis protein that is essential for viability and has ubiquitin-conjugating activity. On initiation of apoptosis, the ubiquitin ligase Nrdp1/RNF41 promotes proteasomal degradation of BRUCE. Here we demonstrate that BRUCE together with the proteasome activator PA28γ causes proteasomal degradati...
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Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with i...
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Considerable progress has been made in understanding the contribution of E3 ubiquitin ligases to health and disease, including the pathogenesis of immunological disorders. Ubiquitin ligases exert exquisite spatial and temporal control over protein stability and function, and are thus crucial for the regulation of both innate and adaptive immunity....
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Inhibition of ubiquitin ligases with small molecule remains a very challenging task, given the lack of catalytic activity of the target and the requirement of disruption of its interactions with other proteins. Siah1/2, which are E3 ubiquitin ligases, are implicated in melanoma and prostate cancer and represent high-value drug targets. We utilized...
Article
During an adaptive immune response, activated mature B cells give rise to Ab-secreting plasma cells to fight infection. B cells undergo Ab class switching to produce different classes of Abs with varying effector functions. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is activated during this process, and disrupting mTOR c...
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Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular resp...
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Inflammatory bowel disease (IBD) is prevalent, but the mechanisms underlying disease development remain elusive. We identify a role for the E3 ubiquitin ligase RNF5 in IBD. Intestinal epithelial cells (IECs) express a high level of RNF5, while the colon of Rnf5?/? mice exhibits activated dendritic cells and intrinsic inflammation. Rnf5?/? mice exhi...
Article
One of the remaining challenges in treating melanoma is its strong propensity to metastasize. Thus, there is considerable interest in understanding the alterations that drive progression of the disease. In this issue of Cancer Cell, Shain et al. and Zheng et al. provide insights implicating p16INK4A in melanoma invasiveness.
Article
The purpose of this project is to investigate the feasibility of using small molecules targeting cap-dependent translation to sensitize B cell lymphoma cells to killing by BCL-2 inhibitors (venetoclax/ ABT-199). We hypothesized that diffuse large B-cell lymphoma (DLBCL) cell survival requires cap-dependent translation, which is facilitated by eukar...
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Although numerous pathways are known to control the tumor suppressor protein p53, coordinated regulation of the p53–Notch axis by Numb may have an even more remarkable impact. In this issue, Colaluca at al. (2018. J. Cell Biol.https://doi.org/10.1083/jcb.201709092 ) reveal an unexpected role of a newly characterized Numb splice variant in the regul...
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The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including 顺心彩票ostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of...
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SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multipr...
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Primary and secondary hypertension are major risk factors for cardiovascular disease, the leading cause of death worldwide. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we report an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah...
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Current efforts in precision oncology largely focus on the benefit of genomics-guided therapy. Yet, advances in sequencing techniques provide an unprecedented view of the complex genetic and nongenetic heterogeneity within individual tumors. Herein, we outline the benefits of integrating genomic and transcriptomic analyses for advanced precision on...
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Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries...
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Stringent transcriptional regulation is crucial for normal cellular biology and organismal development. Perturbations in the proper regulation of transcription factors can result in numerous pathologies, including cancer. Thus, understanding how transcription factors are regulated and how they are dysregulated in disease states is key to the therap...
Chapter
Signal transduction pathways are central to all cellular biological processes, as they provide the link between extracellular or intracellular stimuli and an array of regulatory proteins, including protein kinases, ubiquitin ligases, and transcription factors. Given this, it is not surprising that signal transduction pathways are often deregulated...
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The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival...
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To survive inhospitable environments, tumor cells are forced to remodel their signaling pathways by altering transcription, translation, and post-translational modifications. This adaptation is regulated in a spatial and temporal manner and gives rise to individual tumor cells with distinct gene expression and metabolic signatures. Such phenotypic...
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Conjugation of ubiquitin to target proteins is a finely tuned process involving a reaction, culminating in the conjugation of a single ubiquitin (1). The first step is conjugation of a single ubiquitin molecule to the substrate’s protein amino group (monoubiquitination) or to multiple amino groups (multimonoubiquitination), which can remain as it i...
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Oncogene-driven metabolic rewiring is an adaptation to low nutrient and oxygen conditions in the tumor microenvironment that enables cancer cells of diverse origin to hyperproliferate. Aerobic glycolysis and enhanced reliance on glutamine utilization are prime examples of such rewiring. However, tissue of origin as well as specific genetic and epig...
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Melanoma is one of the most lethal cutaneous malignancies, characterized by chemoresistance and a striking propensity to metastasize. The transcription factor ATF2 elicits oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, we show that expression of a transcriptionally inactive form of Atf2 (Atf2Δ8,9) promot...
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Mitochondrial dynamics encompasses processes associated with mitochondrial fission and fusion, affecting their number, degree of biogenesis, and the induction of mitophagy. These activities determine the balance between mitochondrial energy production and cell death programs. Processes governing mitochondrial dynamics are tightly controlled in phys...
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The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevent...
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The HIV1 protease inhibitor nelfinavir is being investigated as a cancer therapeutic. In this issue of Cancer Cell, Smith et al. (2016) report that nelfinavir suppresses MITF expression induced by MAPK pathway inhibition in melanoma cells and sensitizes melanoma cells with NRAS or BRAF plus NRAS mutations to MEK inhibitors.
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Melanoma is one of the most lethal skin cancers worldwide, primarily because of its propensity to metastasize. Thus, the elucidation of mechanisms that govern metastatic propensity is urgently needed. We found that protein kinase C epsilon (PKC epsilon)-mediated activation of activating transcription factor 2 (ATF2) controls the migratory and invas...
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Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targ...
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It is critical to determine mechanisms underlying the ability of cancer cells to metastasize, given that tumor metastasis is responsible for most cancer-related deaths. While solid tumors shed only a minute fraction of cells capable of colonizing distant tissues and forming a secondary tumor, those invasive cells represent a key obstacle for succes...
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In tumor cells the ability to maintain viability over long time periods without proliferation is referred to as a state of dormancy. Maintenance of dormancy is controlled by numerous cellular and environmental factors, from immune surveillance and tumor-stroma interaction to intracellular signaling. Interference of dormancy (to an "awaken" state) i...
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Recent studies highlight the importance of glutamine metabolism in metabolic reprogramming, which underlies cancer cell addiction to glutamine. Examples for the dependence on glutamine metabolism are seen across different tumor types as during different phases of cancer development, progression and response to therapy. In this perspective, we asses...
Article
Ubiquitin ligases are critical components of the ubiquitin proteasome system (UPS), which governs fundamental processes regulating normal cellular 顺心彩票ostasis, metabolism, and cell cycle in response to external stress signals and DNA damage. Among multiple steps of the UPS system required to regulate protein ubiquitination and stability, UBLs defin...
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Cystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs CFTR trafficking and gating. F508del-CFTR mistrafficking may be corrected by acting directly on mutant CFTR itself or by modulating expression/activity of CFTR-interacting proteins, that may thus...
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Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with...
Article
A single exposure of melanoma-prone transgenic neonatal mice to UVB (ultraviolet B) radiation is sufficient to induce melanomas with high penetrance at an early age of onset. Although the mechanisms underlying this outcome remain elusive, the immaturity of either the melanocytes or the immune system may mediate the increased susceptibility of neona...
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Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. Thi...
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The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, a...
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Melanoma development involves members of the AGC kinase family including AKT, PKC and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in ~70% of human me...
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Glutamine dependence is a prominent feature of cancer metabolism, and here we show that melanoma cells, irrespective of their oncogenic background, depend on glutamine for growth. A quantitative audit of how carbon from glutamine is used showed that TCA-cycle-derived glutamate is, in most melanoma cells, the major glutamine-derived cataplerotic out...
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Cellular stress, induced by external or internal cues, activates several well-orchestrated processes aimed at either restoring cellular 顺心彩票ostasis or committing to cell death. Those processes include the unfolded protein response (UPR), autophagy, hypoxia, and mitochondrial function, which are part of the global endoplasmic reticulum (ER) stress (...
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The identification of mutations in the BRAF serine-threonine kinase (BRAF V600E or V600K) as the most common mutation in melanoma has propelled efforts to develop therapies to inhibit BRAF kinase activity. While currently available BRAF inhibitors (BRAFi) offer unprecedented improvement of patient survival and quality of life, those changes are gen...
Article
SUMO (small ubiquitin-related modifier) represents a class of ubiquitin-like proteins that is conjugated, like ubiquitin, by a set of enzymes to cellular regulatory proteins, including oncogenes and tumor suppressor genes, that play key roles in the control of cell growth, differentiation and apoptosis. SUMO conjugation affects substrates’ subcellu...
Article
Phosphoinositide-dependent kinase-1 (PDK-1) phosphorylates members of the AGC kinase superfamily, including AKT and PKC. We recently demonstrated the importance of PDK1 in melanoma development and progression (Oncogene 2013). Genetic ablation of PDK1 in melanocytes effectively delayed melanoma development and inhibited metastasis in a Braf/Cdkn2a m...
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Tumor cells have an altered metabolism that distinguishes it from their normal counterpart. Intriguingly, tumor cells show increased use of glutamine to fuel catabolic processes. Therefore, altered metabolic tumors have been considered as a good target for anticancer therapy. Ring finger protein 5 (RNF5) is an ER membrane-associated ubiquitin E3 li...
Article
The ubiquitin ligases Siah1/2 have been implicated in the control of key cellular pathways, including hypoxia (through the control of prolyl hydroxylase 1/3 stability), mitochondrial fission (through the control of AKAP121 stability) and Ras/Raf signaling (through its control of Sprouty 2 stability). Expression or activity of Siah1/2 is upregulated...
Article
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Malignant melanoma is currently the most lethal skin cancer and comprises approximately 8% of total U.S. cancers cases. Despite the advent of even the most effective targeted monotherapies to date (e.g., mutant B-RAF inhibitors), clinical responses have largely been transient, a...
Article
Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significan...
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Author Summary Maintaining a balanced level of stress (protein folding, reactive oxygen radicals) is important for keeping cellular 顺心彩票ostasis (the ability of a cell to maintain internal equilibrium by adjusting its physiological processes). The accumulation of stress (external or internal) will trigger a well-orchestrated machinery that attempts...
Article
Apoptosis signal-regulating kinase 1 (ASK1, also known as MAP3K5) mediates reactive oxygen species (ROS)-induced cell death. When activated by ROS, ASK1 ultimately becomes ubiquitinated and degraded by the proteasome, a process that is antagonized by the ubiquitin-specific protease USP9X. Using a functional siRNA (small interfering RNA) screen in H...
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Phosphoinositide-dependent kinase-1 (PDK1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and protein kinase C (PKC), and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 express...
Article
Full-text available
The receptor for activated C kinase 1 (RACK1) serves as an adaptor for a number of proteins along the MAPK, protein kinase C, and Src signaling pathways. The abundance and near ubiquitous expression of RACK1 reflect its role in coordinating signaling molecules for many critical biological processes, from mRNA translation to cell motility to cell su...
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The role of Wnt signaling in embryonic development and stem cell maintenance is well established and aberrations leading to the constitutive up-regulation of this pathway are frequent in several types of human cancers. Upon ligand-mediated activation, Wnt receptors promote the stabilization of β-catenin, which translocates to the nucleus and binds...
Article
The E3 ubiquitin ligase Siah regulates key cellular events that are central to cancer development and progression. A promising route to Siah inhibition is disrupting its interactions with adaptor proteins. However, typical of protein-protein interactions, traditional unbiased approaches to ligand discovery did not produce viable hits against this t...
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Autophagy is an evolutionarily conserved intracellular catabolic process that delivers cytoplasmic components to lysosomes for degradation and recycling. Although originally considered to be a non-selective pathway, it is now recognized that autophagy is involved in selective processes, including the turnover of organelles, removal of protein aggre...
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The AKT and NF-κB pathways are central regulators of cellular signaling events at the basis of tumor development and progression. Both pathways are often up-regulated in different tumor types including melanoma. We recently reported the identification of compound 1 (BI-69A11) as inhibitor of the AKT and the NF-κB pathways. Here we describe SAR stud...
Article
The Siah ubiquitin ligases are members of the RING finger E3 ligases. The Siah E3s are conserved from fly to mammals. Primarily implicated in cellular stress responses, Siah ligases play a key role in hypoxia, through the regulation of HIF-1α transcription stability and activity. Concomitantly, physiological conditions associated with varying oxyge...
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Changes in cell adhesion and polarity are closely associated with epithelial cell transformation and metastatic capacity. The tumor suppressor protein ASPP (Apoptosis-Stimulating Proteins of p53) 2 has been implicated in control of cell adhesion and polarity through its effect on the PAR complex. Here we demonstrate that under hypoxic conditions, t...