A5054148814- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- DNA Repair Mechanisms
- Cancer-related Molecular Pathways
- Immunotherapy and Immune Responses
- Cancer-related gene regulation
- CAR-T cell therapy research
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Acute Lymphoblastic Leukemia research
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Carcinogens and Genotoxicity Assessment
- Cytomegalovirus and herpesvirus research
- Lymphoma Diagnosis and Treatment
- Immunodeficiency and Autoimmune Disorders
- RNA modifications and cancer
- Acute Myeloid Leukemia Research
- Chronic Lymphocytic Leukemia Research
- RNA Research and Splicing
- Genetics and Neurodevelopmental Disorders
- Diabetes and associated disorders
- PARP inhibition in cancer therapy
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
Children's Hospital of Philadelphia
2015-2024
University of Pennsylvania
2015-2024
Cancer Research Institute
2008-2017
Cancer Research Institute of the Slovak Academy of Sciences
2009-2015
Philadelphia University
2007-2015
Cancer Genetics (United States)
2013-2015
CURE Childhood Cancer
2013-2014
Broad Institute
2013
Hokkaido University
2013
Massachusetts General Hospital
2003-2013
BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive human leukemias. Sequences within first exon BCR are required to activate transforming potential BCR-ABL. The SH2/SH3 domain-containing GRB-2 protein links kinases Ras signaling. We demonstrate exists complex with vivo. Binding mediated by direct interaction SH2 domain phosphorylated tyrosine, Y177, exon. BCR-ABL-GRB-2 for...
In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form γ-H2AX) in megabase chromatin domains flanking sites damage. To investigate role we generated H2AX-deficient (H2AX Δ / ) mouse embryonic stem (ES) cells. ES cells are viable. However, they highly sensitive to ionizing radiation (IR) and exhibit elevated levels spontaneous IR-induced genomic instability. Notably, is not required for NHEJ per se because support normal...
Abstract Efficient repair of DNA double-strand breaks (DSBs) requires a coordinated Damage Response (DDR), which includes phosphorylation histone H2Ax, forming γH2Ax. This modification spreads beyond the DSB into neighboring chromatin, generating DDR platform that protects against end disassociation and degradation, minimizing chromosomal rearrangements. However, mechanisms determine breadth intensity γH2Ax domains remain unclear. Here, we show contacts site are primary determinants for...
Transforming growth factor beta (TGF-β) is a multifunctional that regulates many aspects of cellular functions. TGF-β signals through heteromeric complex the type I and II receptors. However, molecular mechanism signal transduction by this receptor remains unresolved. The belongs to transmembrane serine-threonine kinase family. A new member family (R4) was identified shown be functional on basis its ability restore TGF-β-induced gene response in mutant cell lines lacking endogenous receptor....
Studies of chimeric mice demonstrated that the core Ig heavy chain ( IgH ) intronic enhancer (iEμ) functions in V(D)J and class switch recombination at locus. To more fully evaluate role this element these other processes, we generated homozygous for germ-line mutations which sequences iEμ (cEμ) were either deleted (cEμ Δ/Δ mice) or replaced with a pgk-Neo R cassette N/N mice). The cEμ had reduced B cell numbers, association impaired D to J H V DJ rearrangement, whereas complete block...
AbstractThe histone H2A variant, H2AX, is a core component of chromatin that phosphorylated in flanking DNA double strand breaks (DSBs). Here, we summarize H2AX functions and outline specific "anchoring" model, can explain the translocation prone phenotype H2AX-deficient H2AX/p53-deficient mice. We also discuss how this model function could account for some aspects genomic instability cancer human phenotypes associated with Ataxia Telangiectasia (AT), Nijmegen Breakage Syndrome (NBS), Like...
Inhibition of cell growth by type beta transforming factor (TGF-beta) occurs in mid-G1 and is associated with decreased G1 cyclin-dependent kinase activity maintenance the retinoblastoma tumor suppressor protein Rb an underphosphorylated, growth-suppressive state. A variety recent experiments suggest that a functional target E2F transcription factor. In addition, effects TGF-beta can be overcome expression viral oncogene products dissociate from Rb-related polypeptides. These results...
Deregulation of cyclin D1 occurs in numerous human cancers through mutations, alternative splicing, and gene amplification. Although cancer-derived mutants are potent oncogenes vitro vivo, the mechanisms whereby they contribute to neoplasia poorly understood. We now provide evidence derived from both mouse models cells revealing that nuclear accumulation catalytically active mutant D1/CDK4 complexes triggers DNA rereplication, resulting Cdt1 stabilization, which turn damage checkpoint...
Ataxia-telangiectasia (A-T) mutated (ATM) kinase signals all three cell cycle checkpoints after DNA double-stranded break (DSB) damage. H2AX, NBS1, and p53 are substrates of ATM involved in ATM-dependent damage responses. We show here that H2AX is dispensable for the activation responses DSB Therefore, functions primarily as a downstream mediator parallel pathway p53. NBS1 appears to function both an activator adapter mediate activities Phosphorylation induced by normal mutant/mutant...
Chromosomal abnormalities are frequently caused by problems encountered during DNA replication. Although the ATR-Chk1 pathway has previously been implicated in preventing collapse of stalled replication forks into double-strand breaks (DSB), importance response to fork ATR-deficient cells not well characterized. Herein, we demonstrate that, upon replication, ATR deficiency leads phosphorylation H2AX ATM and DNA-PKcs focal accumulation Rad51, a marker homologous recombination restart. Because...