DOCSLIB.ORG

Bcr-Abl-Mediated Resistance to Apoptosis Is Independent of Constant Tyrosine-Kinase Activity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bcr-Abl-Mediated Resistance to Apoptosis Is Independent of Constant Tyrosine-Kinase Activity Cell Death and Differentiation (2003) 10, 592–598 & 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00 www.nature.com/cdd Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity AEB Bueno-da-Silva1,2, G Brumatti1,2, FO Russo1,2,3, Introduction DR Green1,3 and GP Amarante-Mendes*,1,2,3 Apoptosis is a genetically controlled form of cell death that 1 plays a fundamental role during the development and in tissue Department of Immunology, Institute of Biomedical Sciences, University of Sa˜o 1 Paulo, Brazil homeostasis in multicellular organisms. During tumorigen- 2 Institute for Investigation in Immunology, Millennium Institute, Brazil esis, the expansion of a transformed cell population is directly 3 La Jolla Institute for Allergy and Immunology, San Diego, CA, USA related to the difference of the rates of proliferation and cell * Corresponding author: GP Amarante-Mendes, Departamento de Imunologia, death presented by these cells.2 Therefore, interference with Instituto de Cieˆncias Biome´dicas, Universidade de Sa˜o Paulo, Av. Prof. Lineu the apoptotic machinery resulting in increased survival ability Prestes, 1730 – Cidade Universita´ria, Sa˜o Paulo, SP – 05508-900 – Brazil. of a certain cell population contributes to the malignant Tel.: +55 11 3091 7362; Fax: +55 11 3091 7224; E-mail: [email protected] phenotype found in some forms of cancer. This seems to be Received 22.7.02; revised 3.12.02; accepted 6.12.02 the case of the Philadelphia (Ph) chromosome-positive Edited by SJ Martin leukemia. Over 95% of cases of chronic myelogenous leukemia (CML) and 15–35% of acute lymphocytic leukemia (ALL) are Abstract associated with the Ph chromosome, the outcome of a Bcr-Abl is one of the most potent antiapoptotic molecules and reciprocal translocation between chromosomes 9 and 22, which generates the chimeric Bcr-Abl molecule with intrinsic is the tyrosine-kinase implicated in Philadelphia (Ph) tyrosine-kinase activity and altered subcellular compartmen- chromosome-positive leukemia. It is still obscure how Bcr- talization.3 Bcr-Abl molecules exist in two major isoforms: a Abl provides the leukemic cell a strong resistance to 210-kDa protein detected in CML and a 185-kDa fusion chemotherapeutic drugs. A rational drug development protein in ALL. In addition, a more rare protein of 230 kDa is produced a specific inhibitor of the catalytic activity of Bcr- associated with some forms of chronic neutrophilic leukemia Abl called STI571. This drug was shown to eliminate Bcr-Abl- (CNL). In every case, Bcr-Abl has been implicated in cellular positive cells both in vitro and in vivo, although resistant cells transformation and inhibition of apoptosis.4–6 may appear in culture and relapse occurs in some patients. In Transformation by Bcr-Abl requires its tyrosine-kinase 7,8 the study described here, Bcr-Abl-positive cells treated with activity as well as the action of the multiple functional domains presented in this molecule to couple downstream tyrosine-kinase inhibitors such as herbimycin A, genistein or 5,9–13 STI571 lost their phosphotyrosine-containing proteins, but signal transduction pathways. Many molecular targets have been described to account, at were still extremely resistant to apoptosis. Therefore, in the least in part, for the resistance to apoptosis found in Bcr-Abl- absence of tyrosine-kinase activity, Bcr-Abl-positive cells positive cells. We have found that Bcr-Abl induces the continue to signal biochemically to prevent apoptosis expression of the antiapoptotic protein Bcl-xL, and that induced by chemotherapeutic drugs. We propose that downregulation of Bcl-xL by antisense oligonucleotides secondary antiapoptotic signals are entirely responsible for partially sensitize Bcr-Abl-positive cells to apoptosis.14 Later, the resistance of Bcr-Abl-positive cells. Precise determination it was shown that Bcr-Abl activates the transcription of bcl-xL of such signals and rational drug development against them through the activation of Stat5.15–17 The PI3K/Akt pathway should improve the means to combat Ph chromosome- was also suggested to participate in the Bcr-Abl-mediated 18,19 positive leukemia. resistance to apoptosis, although it is important to mention that in our experimental system, using HL-60 cells Cell Death and Differentiation (2003) 10, 592–598. doi:10.1038/ bcr-abl sj.cdd.4401210 transfected with p185 , the strong antiapoptotic signal is clearly independent of PI3K activity.20 Another molecule potentially involved in the apoptosis protection found in Bcr- Keywords: apoptosis; Bcr-Abl; leukemia; tyrosine-kinase; Abl-positive cells is the transcription factor NF-kB, which is STI571 implicated in the induction of endogenous caspase inhibitors of the IAP family21 and was shown to be required by Bcr-Abl- Abbreviations: ALL, acute lymphocytic leukemia; CHX, cyclo- mediated transformation.22,23 heximide; CML, chronic myelogenous leukemia; FCS, fetal calf Although many more work has been published on Bcr-Abl- serum; mAb, monoclonal antibody; pAb, polyclonal antibody; pY, mediated signaling cascades, we still know very little about phosphotyrosine; STS, staurosporine; VP16, etoposide; VM26, how this molecule interferes with the apoptotic machinery. In teniposide. particular, it is not known whether Bcr-Abl tyrosine-kinase is required to be constantly active in order to maintain the resistance to apoptosis observed in Bcr-Abl-expressing cells. Therefore, in the present study, we use tyrosine-kinase Bcr-Abl kinase-independent resistance to apoptosis AEB Bueno-da-Silva et al 593 inhibitors to address whether the presence of phosphotyr- Bcr-Abl-mediated resistance to apoptosis is osine (pY)-containing proteins is necessary to prevent preserved in HL-60 cells treated with STI571 apoptosis induced by a variety of apoptogenic insults. Since HL-60.Bcr-Abl cells were still resistant to apoptosis in situations where the level of pY-containing proteins dropped substantially, we decided to broaden our investigation and test whether a specific Bcr-Abl tyrosine-kinase inhibitor would Results provide different results than herbimycin A and genistein. Broad-spectrum inhibitors of tyrosine-kinases STI571 is a very potent Bcr-Abl kinase inhibitor that has been used with great success in clinical trials to treat Ph block phosphotyrosine-containing proteins but chromosome-positive leukemia (reviewed in Mauro and not the resistance to apoptosis of HL-60.Bcr-Abl Druker24). In addition, it has been shown that cell lines cells derived from Ph chromosome-positive leukemia patients die To investigate the role of pY-containing proteins in Bcr-Abl- upon treatment for a few days with STI571.25, 26 mediated resistance to apoptosis, we treated HL-60 and HL- We therefore incubated HL-60 and HL60.Bcr-Abl cells with 60.Bcr-Abl cells with two broad-spectrum tyrosine-kinase 10 mM STI571 and inspected the levels of Bcr-Abl and pY- inhibitors, namely herbimycin A and genistein. Both drugs containing proteins after 2 and 24 h. As we can see in Figure 3, were able to inhibit the appearance of pY-containing proteins HL-60 cells are very meager in pY-containing proteins. In in a dose-dependent manner, as assessed by Western blots contrast, HL-60.Bcr-Abl exhibited a great amount of these using anti-pY antibodies. Herbimycin A was most efficient at molecules, which disappeared after 2 h in the presence of 100 ng/ml (Figure 1a), whereas genistein was capable to STI571 and remained almost undetectable at least for the significantly reduce the levels of pY-containing proteins at following 22 h. With these results in mind, we pretreated HL- 250 mg/ml (Figure 2a). Incubation for 24 h with either 60 and HL60.Bcr-Abl cells with STI571 for 2 h and then herbimycin A or genistein alone did not induce cell death in incubated each of them in the presence or absence of VM26, both HL-60 and HL-60.Bcr-Abl cells (Figures 1b and 2b, left VP16, CHX or STS for 22 h. At the end of the assay, we panels). Interestingly, even in the presence of 100 ng/ml evaluated the level of apoptosis in each experimental situation herbimycin A (Figure 1b, center and right panels) or 250 mg/ml by quantify phosphatidylserine externalization. Although the genistein (Figure 2b, center and right panels), HL-60.Bcr-Abl STI571 blocked the Bcr-Abl tyrosine-kinase activity, and the cells were extremely resistant to apoptosis induced by 100 mM consequent appearance of pY-containing proteins, prior to CHX or 50 mM VP16. apoptogenic drug administration, it did not interfere with the resistance to apoptosis of HL-60.Bcr-Abl for the following 22 h (Figure 4). a HL-60 HL-60.Bcr-Abl Herbimycin A: 00 110100 (ng/ml) a HL-60.Bcr-Abl Anti-PY Genistein: 0 2 10 50 250 (µg/ml) Anti-PY b HL-60 HL-60.Bcr-Abl b HL-60 100 Untreated100 CHX 100 VP16 HL-60.Bcr-Abl 100 100 100 80 80 80 Untreated CHX VP16 80 80 80 60 60 60 60 60 60 40 40 40 40 40 40 % apoptosis 20 20 20 % apoptosis 20 20 20 0 0 0 0 0 0 1 10 100 01 10 100 0 1 10 100 0 100 101 102 103 100 101 102 103 100 101 102 103 Herbimycin A (ng/ml) Genistein (µg/ml) Figure 1 Herbimycin A inhibits pY-containing proteins but does not interfere Figure 2 Genistein inhibits pY-containing proteins but does not interfere with with the resistance of HL-60.Bcr-Abl cells. HL-60 and HL-60.Bcr-Abl cells were the resistance of HL-60.Bcr-Abl cells. HL-60 and HL-60.Bcr-Abl cells were pretreated for 1 h with different concentration of herbimycin A (a) and pretreated for 45 min with different concentration of genistein (a) and subsequently incubated overnight in the presence of 100 mM CHX or 50 mM subsequently incubated overnight in the presence of 100 mM CHX or 50 mM VP-16 (b).
Load more

Recommended publications
  • Andrew Goldstein, Ph.D., Is an Assistant Professor Of
    Andrew S. Goldstein, Ph.D. Biography: Andrew Goldstein, Ph.D., is an Assistant Professor of Molecular, Cell and Developmental Biology and Assistant Professor of Urology in the David Geffen School of Medicine at the University of California, Los Angeles. Dr. Goldstein is a member of the Broad Stem Cell Research Center and the Jonsson Comprehensive Cancer Center at UCLA. Dr. Goldstein majored in Biochemistry and Molecular Biology at Dartmouth College before receiving his Ph.D. in Molecular Biology under the mentorship of Dr. Owen Witte at UCLA. He went on to start his own research group as a Fellow of the Broad Stem Cell Research Center at UCLA in 2011 before joining the faculty as an Assistant Professor in 2016. Dr. Goldstein’s research has been supported by a Prostate Cancer Foundation Young Investigator Award, Department of Defense PCRP Idea Development Award and an American Cancer Society Research Scholar Grant, and his work is currently supported by an NIH/NCI R01. He has been awarded the 2018 American Cancer Society Giants of Science Hope Award, 2019 SBUR Young Investigator Award and 2019 Rose Hills Innovator Award. At UCLA, Dr. Goldstein serves on committees for the Jonsson Comprehensive Cancer Center, the SPORE in Prostate Cancer, and the graduate program in Cell and Developmental Biology. He joined the Society for Basic Urologic Research in 2019 and currently participates as part of the membership committee (2020-present). Research Interests: Research in Dr. Goldstein’s laboratory is focused on defining factors that regulate prostate progenitor cell aging and transformation with an emerging interest in prostate epithelial metabolism.
    [Show full text]
  • UNIVERSITY of CALIFORNIA Los Angeles Gene Editing of Bruton's
    UNIVERSITY OF CALIFORNIA Los Angeles Gene Editing of Bruton’s Tyrosine Kinase for Treatment of X-Linked Agammaglobulinemia A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular Biology by David Gray 2020 © Copyright by David Gray 2020 ABSTRACT OF THE DISSERTATION Gene Editing of Bruton’s Tyrosine Kinase for Treatment of X-Linked Agammaglobulinemia by David Gray Doctor of Philosophy in Molecular Biology University of California, Los Angeles, 2020 Professor Donald Barry Kohn, Chair X-Linked Agammaglobulinemia (XLA) is a primary immunodeficiency characterized by a lack of mature B lymphocytes and antibody production. Patients with XLA have loss of function mutations in the Bruton’s Tyrosine Kinase (BTK) gene. The standard of care for XLA is immunoglobulin supplementation, which has a profound effect on patient wellbeing and life expectancies. However, immunoglobulin supplementation requires frequent, expensive injections throughout a patient’s life and patients remain susceptible to certain recurring illnesses. The only permanent cure for XLA is an allogeneic hematopoietic stem cell (HSC) transplant, though it is rarely performed due to the associated risks. Gene therapy-based methods to replace or repair the BTK gene in autologous HSCs provide an alternative with the benefits of a permanent cure for XLA while circumventing much of the risk. While previous efforts to deliver a functional copy of the BTK gene using viral vector mediated gene transfer have shown promise, these vectors carry a risk of insertional oncogenesis ii which may not be tolerated for treatment of XLA. Instead, this dissertation lays a foundation for targeted integration of a functional copy of the BTK gene into HSCs using Cas9 endonuclease mediated gene editing to drastically reduce those risks.
    [Show full text]
  • UCLA Electronic Theses and Dissertations
    UCLA UCLA Electronic Theses and Dissertations Title Non-mutated kinases in prostate cancer metastasis: drivers and therapeutic targets Permalink https://escholarship.org/uc/item/7615v8xd Author Faltermeier, Claire Publication Date 2016 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA Los Angeles Non-mutated kinases in metastatic prostate cancer: drivers and therapeutic targets A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular Biology by Claire Faltermeier 2016 © Copyright by Claire Faltermeier 2016 ABSTRACT OF THE DISSERTATION Non-mutated kinases in prostate cancer: drivers and therapeutic targets by Claire Faltermeier Doctor of Philosophy in Molecular Biology University of California, Los Angeles, 2016 Professor Hanna K. A. Mikkola, Chair Metastatic prostate cancer lacks effective treatments and is a major cause of death in the United States. Targeting mutationally activated protein kinases has improved patient survival in numerous cancers. However, genetic alterations resulting in constitutive kinase activity are rare in metastatic prostate cancer. Evidence suggests that non-mutated, wild-type kinases are involved in advanced prostate cancer, but it remains unknown whether kinases contribute mechanistically to metastasis and should be pursued as therapeutic targets. Using a mass- spectrometry based phosphoproteomics approach, we identified tyrosine, serine, and threonine kinases
    [Show full text]
  • Inner Workings: Tyrosine Kinases, Their Discovery and Impact
    INNER WORKINGS Inner Workings: Tyrosine kinases, their discovery and impact Jessica Marshall Science Writer At the same time, Witte and his colleagues reported that the cancer-causing Abelson virus, which acts in mice, worked via another protein that added a phosphorous to tyro- While working in his laboratory at the Salk as a protein kinase: an enzyme that adds sine. But, this occurred through self-phos- Institute in 1979, Tony Hunter took a a phosphate to another protein (2). The phorylation (4). shortcut. Hunter decided not to make up buffer’s pH had fallen slightly as it sat on Tyrosine kinases act as a signal relay that freshbufferforhiselectrophoresisrun.That the bench, which caused two amino acids— control many cellular pathways, including cell decision would alter his career, significantly phosphothreonine and phosphotyrosine—to growth. When the kinases become mutated influence the field of cancer biology, and separate from each other on the electropho- in cancer, cell division spirals out of control. ultimately lead to new cancer treatments. resis plate, when normally they would have This understanding ultimately led to the Hunter was studying Rous sarcoma virus, run together. This separation revealed that development of a whole new class of cancer the first known cancer-causing virus, reported the target for the cancer-causing protein drugs known as tyrosine kinase inhibitors. in 1911 by Peyton Rous, who showed it kinase was tyrosine. “People immediately realized that many caused cancer in chickens. Rous’sdiscovery, It was the first report of a tyrosine kinase kinases may be tyrosine kinases,” says Stanley which earned him the Nobel Prize in 1966, (3), a class of proteins that would prove to be Lipkowitz of the National Cancer Institute.
    [Show full text]
  • Profile of Charles L. Sawyers
    PROFILE Profile of Charles L. Sawyers harles Sawyers is a rock star in his Ras, a handful of research teams across own right. Last year, Sawyers, the country were hot on the trail of other Cchair of the Human Oncology oncogenes. Witte focused on the Phila- and Pathogenesis Program at delphia Chromosome, a genetic aberra- Memorial Sloan–Kettering Cancer Center tion that juxtaposes two genes, dubbed and a member of the National Academy BCR and ABL, when human chromo- of Sciences, posed with singer Debbie somes 9 and 22 swap segments, producing Harry of the rock band Blondie to pro- a hybrid enzyme in blood cells that jams mote cancer research in a campaign the cells’ growth restraints and leads to sponsored by the Geoffrey Beene Cancer CML. Patients with CML have a pro- Research Center. The unlikely assemblage fusion of frenetically dividing white blood of rock star and researcher shined the cells. Left unchecked, the disease can kill spotlight on pioneering efforts in trans- within 3 years of diagnosis. “This was an lational cancer research. Few physicians example of a cancer where the genetic deserve that spotlight more than Sawyers, abnormality was clear. That’s what at- who co-discovered the targeted cancer tracted me to Owen’s lab,” says Sawyers, drug, Gleevec, forging a path to cancer who joined the laboratory as a post- treatment that has now become increas- doctoral fellow in 1989. That move was ingly common. merely the opening act to a career punc- Born to physicians who served as a tuated by startling revelations, fruitful source of inspiration, Sawyers grew up in partnerships, life-saving discoveries, and a Nashville, Tennessee household where even heart-wrenching disappointments.
    [Show full text]
  • Profile of Charles L. Sawyers
    PROFILE Profile of Charles L. Sawyers harles Sawyers is a rock star in his Ras, a handful of research teams across own right. Last year, Sawyers, the country were hot on the trail of other Cchair of the Human Oncology oncogenes. Witte focused on the Phila- and Pathogenesis Program at delphia Chromosome, a genetic aberra- Memorial Sloan–Kettering Cancer Center tion that juxtaposes two genes, dubbed and a member of the National Academy BCR and ABL, when human chromo- of Sciences, posed with singer Debbie somes 9 and 22 swap segments, producing Harry of the rock band Blondie to pro- a hybrid enzyme in blood cells that jams mote cancer research in a campaign the cells’ growth restraints and leads to sponsored by the Geoffrey Beene Cancer CML. Patients with CML have a pro- Research Center. The unlikely assemblage fusion of frenetically dividing white blood of rock star and researcher shined the cells. Left unchecked, the disease can kill spotlight on pioneering efforts in trans- within 3 years of diagnosis. “This was an lational cancer research. Few physicians example of a cancer where the genetic deserve that spotlight more than Sawyers, abnormality was clear. That’s what at- who co-discovered the targeted cancer tracted me to Owen’s lab,” says Sawyers, drug, Gleevec, forging a path to cancer who joined the laboratory as a post- treatment that has now become increas- doctoral fellow in 1989. That move was ingly common. merely the opening act to a career punc- Born to physicians who served as a tuated by startling revelations, fruitful source of inspiration, Sawyers grew up in partnerships, life-saving discoveries, and a Nashville, Tennessee household where even heart-wrenching disappointments.
    [Show full text]
  • Tyrosine Kinases, Their Discovery and Impact
    INNER WORKINGS Inner Workings: Tyrosine kinases, their discovery and impact Jessica Marshall Science Writer At the same time, Witte and his colleagues reported that the cancer-causing Abelson virus, which acts in mice, worked via another protein that added a phosphorous to tyro- While working in his laboratory at the Salk as a protein kinase: an enzyme that adds sine. But, this occurred through self-phos- Institute in 1979, Tony Hunter took a a phosphate to another protein (2). The phorylation (4). shortcut. Hunter decided not to make up buffer’s pH had fallen slightly as it sat on Tyrosine kinases act as a signal relay that freshbufferforhiselectrophoresisrun.That the bench, which caused two amino acids— control many cellular pathways, including cell decision would alter his career, significantly phosphothreonine and phosphotyrosine—to growth. When the kinases become mutated influence the field of cancer biology, and separate from each other on the electropho- in cancer, cell division spirals out of control. ultimately lead to new cancer treatments. resis plate, when normally they would have This understanding ultimately led to the Hunter was studying Rous sarcoma virus, run together. This separation revealed that development of a whole new class of cancer the first known cancer-causing virus, reported the target for the cancer-causing protein drugs known as tyrosine kinase inhibitors. in 1911 by Peyton Rous, who showed it kinase was tyrosine. “People immediately realized that many caused cancer in chickens. Rous’sdiscovery, It was the first report of a tyrosine kinase kinases may be tyrosine kinases,” says Stanley which earned him the Nobel Prize in 1966, (3), a class of proteins that would prove to be Lipkowitz of the National Cancer Institute.
    [Show full text]
  • UNIVERSITY of CALIFORNIA Los Angeles Non-Mutated Kinases in Metastatic Prostate Cancer
    UNIVERSITY OF CALIFORNIA Los Angeles Non-mutated kinases in metastatic prostate cancer: drivers and therapeutic targets A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular Biology by Claire Faltermeier 2016 © Copyright by Claire Faltermeier 2016 ABSTRACT OF THE DISSERTATION Non-mutated kinases in prostate cancer: drivers and therapeutic targets by Claire Faltermeier Doctor of Philosophy in Molecular Biology University of California, Los Angeles, 2016 Professor Hanna K. A. Mikkola, Chair Metastatic prostate cancer lacks effective treatments and is a major cause of death in the United States. Targeting mutationally activated protein kinases has improved patient survival in numerous cancers. However, genetic alterations resulting in constitutive kinase activity are rare in metastatic prostate cancer. Evidence suggests that non-mutated, wild-type kinases are involved in advanced prostate cancer, but it remains unknown whether kinases contribute mechanistically to metastasis and should be pursued as therapeutic targets. Using a mass- spectrometry based phosphoproteomics approach, we identified tyrosine, serine, and threonine kinases that are differentially activated in human metastatic prostate cancer tissue specimens compared to localized disease. To investigate the functional role of these kinases in prostate cancer metastasis, we screened over 100 kinases identified from our phosphoproteomic and previously-published transcriptomic studies for their ability to drive metastasis. In a primary ii screen using a lung colonization assay, we identified 20 kinases that when overexpressed in murine prostate cancer cells could promote metastasis to the lungs with different latencies. We queried these 20 kinases in a secondary in vivo screen using non-malignant human prostate cells.
    [Show full text]
  • V-Src Oncogene Induces Trop2 Proteolytic Activation Via Cyclin D1
    Thomas Jefferson University Jefferson Digital Commons Department of Cancer Biology Faculty Papers Department of Cancer Biology 11-15-2016 v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1. Xiaoming Ju Thomas Jefferson University Xuanmao Jiao Thomas Jefferson University Adam Ertel Thomas Jefferson University Mathew C. Casimiro Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/cbfp Gabriele Disante Thomas Part ofJeff theerson Oncology University Commons Let us know how access to this document benefits ouy See next page for additional authors Recommended Citation Ju, Xiaoming; Jiao, Xuanmao; Ertel, Adam; Casimiro, Mathew C.; Disante, Gabriele; Deng, Shengqiong; Li, Zhiping; Di Rocco, Agnese; Zhan, Tingting; Hawkins, Adam; Stoyanova, Tanya; Andò, Sebastiano; Fatatis, Alessandro; Lisanti, Michael P.; Gomella, Leonard G.; Languino, Lucia R.; and Pestell, Richard G., "v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1." (2016). Department of Cancer Biology Faculty Papers. Paper 128. https://jdc.jefferson.edu/cbfp/128 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Cancer Biology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected].
    [Show full text]
  • Gleevec's Glory Days
    Diabetes Detectives || $$$ to Databases || Anthrax 101 || Fighting Parasites in Bangladesh DECEMBER 2001 Gleevec’s Glory Days The Long Journey of a Celebrated Anticancer Drug FEATURES Gleevec’s Glory Days Mirpur’s Children 10 22 An apparent overnight success, this new A slum in Bangladesh yields clues about leukemia drug has decades of research behind it. immunity, infection and an illness that afflicts By Jill Waalen millions worldwide. By David Jarmul 16 Confronting Diabetes From All Angles 26 Scientific Outliers To combat this growing epidemic, researchers are hunting for genes, exploring cell-signaling How teachers and students in rural America pathways and looking at obesityÕs role. can learn good science. By Karen Hopkin By Mitch Leslie 16 In Starr County, Texas, an alarming 2,500 Mexican- American residents have type 2 diabetes. These women, at the Starr County Health Studies Office, undergo regular monitoring of their disease, which has strong genetic and evironmental components. DEPARTMENTS 2 NOTA BENE 30 HANDS ON Howard Hughes Medical Institute Bulletin ulletin Building Interest in the December 2001 || Volume 14 Number 5 3 PRESIDENT’S LETTER Human Body HHMI TRUSTEES Biomedical Research in a James A. Baker, III, Esq. Changed World Senior Partner, Baker & Botts NEWS AND NOTES Alexander G. Bearn, M.D. Executive Officer, American Philosophical Society 32 To Think Like a Scientist Adjunct Professor, The Rockefeller University UP FRONT Professor Emeritus of Medicine, Cornell University Medical College Frank William Gay 4 Mouse Model Closely 33 Undergraduate Taps Into Former President and Chief Executive Officer, summa Corporation James H. Gilliam, Jr., Esq. Mimics Human Cancer Tomato Communication Former Executive Vice President and General Counsel, Beneficial Corporation 6 Database Science Forcing New Hanna H.
    [Show full text]
  • Lysine Acetylation Regulates Bruton's Tyrosine Kinase in B Cell
    Lysine Acetylation Regulates Bruton's Tyrosine Kinase in B Cell Activation Zhijian Liu, Antonello Mai and Jian Sun This information is current as J Immunol 2010; 184:244-254; Prepublished online 30 of September 27, 2021. November 2009; doi: 10.4049/jimmunol.0902324 http://www.jimmunol.org/content/184/1/244 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2009/12/11/jimmunol.090232 Material 4.DC1 References This article cites 44 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/184/1/244.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Lysine Acetylation Regulates Bruton’s Tyrosine Kinase in B Cell Activation Zhijian Liu,*,†,‡ Antonello Mai,‡,x and Jian Sun*,{ Bruton’s tyrosine kinase (Btk) is essential for BCR signal transduction and has diverse functions in B cells.
    [Show full text]
  • Mechanistic Insight Into the Regulation of Tec Family Kinase Activity - Substrate Selection and Conformational Preferences Qian Xie Iowa State University
    Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2014 Mechanistic insight into the regulation of Tec family kinase activity - substrate selection and conformational preferences Qian Xie Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Biochemistry Commons, and the Biophysics Commons Recommended Citation Xie, Qian, "Mechanistic insight into the regulation of Tec family kinase activity - substrate selection and conformational preferences" (2014). Graduate Theses and Dissertations. 13715. https://lib.dr.iastate.edu/etd/13715 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Mechanistic insight into the regulation of Tec family kinase activity − substrate selection and conformational preferences by Qian Xie A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Biochemistry Program of Study Committee: Amy Andreotti, Major Professor Mark Hargrove Richard Honzatko Michael Shogren-Knaak Edward Yu Iowa State University Ames, Iowa 2014 Copyright © Qian Xie, 2014. All rights reserved. ii TABLE OF CONTENTS CHAPTER 1. GENERAL INTRODUCTION Literature Review 1 Thesis Organization 11 Motivation 12 References 12 CHAPTER 2. SUBSTRATE RECOGNITION OF PLCγ1 VIA A SPECIFIC DOCKING SURFACE ON ITK Abstract 15 Introduction 16 Results 19 Discussion 27 Materials and Methods 31 Acknowledgements 35 References 35 Figure Captions 38 Figures 44 CHAPTER 3.
    [Show full text]