Joo E.J.,Seoul National University |
Joo E.J.,Leukemia Research Program |
Chun J.,Seoul National University |
Ha Y.W.,Samsung |
And 3 more authors.
Chemico-Biological Interactions | Year: 2015
Ginsenoside Rg3 (Rg3), a pharmacologically active compound from red ginseng, has been reported to induce cell death in various cancer cell lines, although the specific mechanisms have not been well established. In the present study, Rg3 treatment to A549 human lung adenocarcinoma led to cell death via not only apoptotic pathways but also the downregulation of epidermal growth factor receptor (EGFR). We used cross-linker and cell enzyme-linked immunosorbent assays to show that Rg3 inhibited EGFR dimerization by EGF stimulation and caused EGFR internalization from the cell membrane. Among several important phosphorylation sites in cytoplasmic EGFR, Rg3 increased the phosphorylation of tyrosine 1045 (pY1045) and serine 1046/1047 (pS1046/1047) for EGFR degradation and coincidently, attenuated pY1173 and pY1068 for mitogen-activated protein kinase activity. These effects were amplified under EGF-pretreated Rg3 stimulation. In vivo experiments showed that the average volume of the tumors treated with 30 mg/kg of Rg3 was significantly decreased by 40% compared with the control. Through immunohistochemistry, we detected the fragmentation of DNA, the accumulation of Rg3, and the reduction of EGFR expression in the Rg3-treated groups. Here, we provide the first description of the roles of Rg3 in the reduction of cell surface EGFR, the attenuation of EGFR signal transduction, and the eventual activation of apoptosis in A549 human lung adenocarcinoma. © 2015 Elsevier Ireland Ltd. All rights reserved.
Jiang X.-X.,University of Southern California |
Nguyen Q.,University of Southern California |
Chou Y.,University of Southern California |
Wang T.,University of Southern California |
And 10 more authors.
Immunity | Year: 2011
Epigenetic histone modifications play critical roles in the control of gene transcription. Recently, an increasing number of histone H2A deubiquitinases have been identified and characterized. However, the physiological functions for this entire group of histone H2A deubiquitinases remain unknown. In this study, we revealed that the histone H2A deubiquitinase MYSM1 plays an essential and intrinsic role in early B cell development. MYSM1 deficiency results in a block in early B cell commitment and a defect of B cell progenitors in expression of EBF1 and other B lymphoid genes. We further demonstrated that MYSM1 derepresses EBF1 transcription in B cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus. Thus, this study not only uncovers the essential role for MYSM1 in gene transcription during early B cell development but also underscores the biological significance of reversible epigenetic histone H2A ubiquitination. © 2011 Elsevier Inc.
Fei F.,Saban Research Institute |
Kweon S.-M.,Saban Research Institute |
Kweon S.-M.,Leukemia Research Program |
Haataja L.,University of Michigan |
And 5 more authors.
BMC Biochemistry | Year: 2010
Background: RhoGDIα proteins are important regulators of the small GTPase Rac, because they shuttle Rac from the cytoplasm to membranes and also protect Rac from activation, deactivation and degradation. How the binding and release of Rac from RhoGDIα is regulated is not precisely understood. Results. We report that the non-receptor tyrosine kinase Fer is able to phosphorylate RhoGDIα and form a direct protein complex with it. This interaction is mediated by the C-terminal end of RhoGDIα. Activation of Fer by reactive oxygen species caused increased phosphorylation of RhoGDIα and pervanadate treatment further augmented this. Tyrosine phosphorylation of RhoGDIα by Fer prevented subsequent binding of Rac to RhoGDIα, but once a RhoGDIα-Rac complex was formed, the Fer kinase was not able to cause Rac release through tyrosine phosphorylation of preformed RhoGDIα-Rac complexes. Conclusions. These results identify tyrosine phosphorylation of RhoGDIα by Fer as a mechanism to regulate binding of RhoGDIα to Rac. © 2010 Fei et al; licensee BioMed Central Ltd.
Arutyunyan A.,Saban Research Institute |
Stoddart S.,Saban Research Institute |
Yi S.-J.,Saban Research Institute |
Fei F.,Saban Research Institute |
And 10 more authors.
BMC Genomics | Year: 2012
Background: Acute lymphoblastic leukemia (ALL) cells treated with drugs can become drug-tolerant if co-cultured with protective stromal mouse embryonic fibroblasts (MEFs).Results: We performed transcriptional profiling on these stromal fibroblasts to investigate if they were affected by the presence of drug-treated ALL cells. These mitotically inactivated MEFs showed few changes in gene expression, but a family of sequences of which transcription is significantly increased was identified. A sequence related to this family, which we named cassini, was selected for further characterization. We found that cassini was highly upregulated in drug-treated ALL cells. Analysis of RNAs from different normal mouse tissues showed that cassini expression is highest in spleen and thymus, and can be further enhanced in these organs by exposure of mice to bacterial endotoxin. Heat shock, but not other types of stress, significantly induced the transcription of this locus in ALL cells. Transient overexpression of cassini in human 293 embryonic kidney cells did not increase the cytotoxic or cytostatic effects of chemotherapeutic drugs but provided some protection. Database searches revealed that sequences highly homologous to cassini are present in rodents, apicomplexans, flatworms and primates, indicating that they are conserved in evolution. Moreover, CASSINI RNA was induced in human ALL cells treated with vincristine. Surprisingly, cassini belongs to the previously reported murine family of γ-satellite/major satellite DNA sequences, which were not known to be present in other species.Conclusions: Our results show that the transcription of at least one member of these sequences is regulated, suggesting that this has a function in normal and transformed immune cells. Expression of these sequences may protect cells when they are exposed to specific stress stimuli. © 2012 Arutyunyan et al.; licensee BioMed Central Ltd.
Parameswaran R.,Section of Molecular Carcinogenesis |
Yu M.,Section of Molecular Carcinogenesis |
Lyu M.-A.,University of Texas M. D. Anderson Cancer Center |
Lim M.,Section of Molecular Carcinogenesis |
And 7 more authors.
Leukemia | Year: 2012
Acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children and a major cause of mortality from hematopoietic malignancies in adults. A substantial number of patients become drug resistant during chemotherapy, necessitating the development of alternative modes of treatment. rGel (recombinant Gelonin)/BlyS (B-lymphocyte stimulator) is a toxin-cytokine fusion protein used for selective killing of malignant B-cells expressing receptors for B-cell-activating factor (BAFF/BLyS) by receptor-targeted delivery of the toxin, Gelonin. Here, we demonstrate that rGel/BLyS binds to ALL cells expressing BAFF receptor (BAFF-R) and upon internalization, it induces apoptosis of these cells and causes downregulation of survival genes even in the presence of stromal protection. Using an immunodeficient transplant model for human ALL, we show that rGel/BLyS prolongs survival of both Philadelphia chromosome-positive and negative ALL-bearing mice. Furthermore, we used AMD3100, a CXCR4 antagonist, to mobilize the leukemic cells protected in the bone marrow (BM) microenvironment and the combination with rGel/BLyS resulted in a significant reduction of the tumor load in the BM and complete eradication of ALL cells from the circulation. Thus, a combination treatment with the B-cell-specific fusion toxin rGel/BLyS and the mobilizing agent AMD3100 could be an effective alternative approach to chemotherapy for the treatment of primary and relapsed ALL. © 2012 Macmillan Publishers Limited.