A5091416572- Cell death mechanisms and regulation
- Chronic Myeloid Leukemia Treatments
- Protein Degradation and Inhibitors
- Protein Kinase Regulation and GTPase Signaling
- Chronic Lymphocytic Leukemia Research
- Melanoma and MAPK Pathways
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- FOXO transcription factor regulation
- RNA Interference and Gene Delivery
- NF-κB Signaling Pathways
- Autophagy in Disease and Therapy
- Angiogenesis and VEGF in Cancer
- Histone Deacetylase Inhibitors Research
- Cellular transport and secretion
- Ubiquitin and proteasome pathways
- Acute Lymphoblastic Leukemia research
- Mitochondrial Function and Pathology
- Synthesis and Characterization of Heterocyclic Compounds
- Cell Adhesion Molecules Research
- interferon and immune responses
- Pancreatic and Hepatic Oncology Research
- Phagocytosis and Immune Regulation
- Virus-based gene therapy research
- Lipid Membrane Structure and Behavior
Beth Israel Deaconess Medical Center
2011-2023
Harvard University
2010-2023
Beth Israel Deaconess Hospital
2007-2014
University of Pittsburgh
2014
Ziopharm Oncology (United States)
2013
Hadassah Medical Center
2005-2011
Massachusetts General Hospital
2007
Harvard University Press
2002-2003
Massachusetts Institute of Technology
1997-2003
Whitehead Institute for Biomedical Research
2003
Human Protein Reference Database (HPRD) is an object database that integrates a wealth of information relevant to the function human proteins in health and disease. Data pertaining thousands protein-protein interactions, posttranslational modifications, enzyme/substrate relationships, disease associations, tissue expression, subcellular localization were extracted from literature for nonredundant set 2750 proteins. Almost all was obtained manually by biologists who read interpreted >300,000...
Although substantial evidence supports a critical role for the activation of Raf-1 and mitogen-activated protein kinases (MAPKs) in oncogenic Ras-mediated transformation, recent suggests that Ras may activate second signaling pathway which involves Ras-related proteins Rac1 RhoA. Consequently, we used three complementary approaches to determine contribution RhoA function transformation. First, whereas constitutively activated mutants showed very weak transforming activity when transfected...
We have examined the role of ras-related rab proteins in transport from ER to Golgi complex vivo using a vaccinia recombinant T7 RNA polymerase virus express site-directed mutants. These mutations are within highly conserved domains involved guanine nucleotide binding and hydrolysis found ras all members superfamily. Substitutions GTP-binding rab1a rab1b (equivalent 17N 116I mutants) resulted which were potent trans dominant inhibitors vesicular stomatitis glycoprotein (VSV-G protein)...
Mitogen-activated protein (MAP) kinases can be grouped into three structural families, ERK, JNK, and p38, which are thought to carry out unique functions within cells. We demonstrate that p38 activated by distinct combinations of stimuli in T cells simulate full or partial activation through the cell receptor. These regulated reversible phosphorylation on Tyr Thr, dual specific phosphatases PAC1 MKP-1 previously have been implicated vivo inactivation ERK respectively. Here we characterize a...
We report an essential role for the ras-related small GTP-binding protein rab1b in vesicular transport mammalian cells. mAbs detect both ER and Golgi compartments. Using assay which reconstitutes between cis-Golgi compartment, we find that is required during initial step export of from ER. In addition, it also successive cis- medial-Golgi suggest may provide a common link upstream downstream components fission fusion machinery functioning early compartments secretory pathway.
Substantial evidence supports a critical role for the activation of Raf-1/MEK/mitogen-activated protein kinase pathway in oncogenic Ras-mediated transformation. For example, dominant negative mutants Raf-1, MEK, and mitogen-activated all inhibit Ras Furthermore, observation that plasma membrane-localized Raf-1 exhibits same transforming potency as suggests alone is sufficient to mediate full activity. However, recent identification other candidate effectors (e.g., RalGDS...
Vav is a member of family oncogene proteins that share an approximately 250-amino-acid motif called Dbl homology domain. Paradoxically, itself and other containing domain catalyze GTP-GDP exchange for Rho proteins, whereas has been reported to Ras proteins. We present Saccharomyces cerevisiae genetic data, in vitro biochemical animal cell biological data indicating guanine nucleotide factor Rho-related but similar experiments we fail find evidence Ras. Further, the Lck kinase activates...
Mevalonate starvation of hamster fibroblasts resulted in a shift rab1b from the membrane to cytosolic fraction, suggesting that depends upon an isoprenoid modification for its localization. and rab3a proteins expressed insect cells incorporated product [3H]mevalonate, gas chromatography analysis material released by Raney nickel cleavage demonstrated are modified geranylgeranyl groups. Additionally, vitro prenylation farnesyl H-ras but five rab (1a, 1b, 2, 3a, 6). Together, these results...
Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in a variety of tumorigenic and transformed cell lines but not many normal cells. Hence, TRAIL the potential be an ideal cancer therapeutic agent with minimal cytotoxicity. FLICE inhibitory protein (c-FLIP) is important regulator TRAIL-induced apoptosis. Here, we show that persistent expression c-FLIP(Long) [c-FLIP(L)] inversely correlated ability prostate In contrast TRAIL-sensitive...
Cytokine-provided survival signals are known to suppress apoptosis through inhibition of mitochondrial pathways that involve Bcl-2 family members. Here we show in hematopoietic cells, cytokines also regulate death receptor-mediated pathways. We demonstrate such as IL-3 and erythropoietin normal well BCR-ABL oncoprotein transformed inhibit transcription tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Using small interfering RNAs, the TRAIL function is sufficient partially...
Although Raf-1 is a critical Ras effector target, how mediates activation remains unresolved. residues 55-131 define Ras-binding domain essential for activation. Therefore, our identification of second site in the cysteine-rich (residues 139-184) was unexpected and suggested more complex role Both recognition domains preferentially associate with Ras-GTP. mutations that impair activity by perturbing regions distinguish Ras-GDP from Ras-GTP (switch I II) may disrupt interactions either...
Vav and Dbl are members of a novel class oncogene proteins that share significant sequence identity in approximately 250-amino-acid domain, designated the homology domain. Although functions as guanine nucleotide exchange factor (GEF) activator Rho family proteins, recent evidence has demonstrated GEF for Ras proteins. Thus, transformation by may be consequence constitutive activation respectively. To address this possibility, we have compared transforming activities with GEF, GRF/CDC25. As...
Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, role protein phosphatases (PP) in control localization function unknown. In this study, we detected robust interaction between PP2A. We further demonstrate that 14-3-3, while not impeding PP2A restrains its toward AKT sites T32/S253. Disruption revealed after inhibition,...