Academic Appointments

Honors & Awards

  • Scholar Award, The V Foundation for Cancer Research (2012-2013)
  • Scholar Award, Baxter Foundation (2011)
  • Genentech Postdoctoral Fellowship, Massachusetts Institute of Technology (2009-2010)
  • Damon Runyon Cancer Research Foundation, Fellowship (2006-2009)
  • Hugh McDevitt Prize in Immunology, Stanford University (2006)
  • Pre-Doctoral Fellowship, Howard Hughes Medical Institute (2001-2006)
  • Stanford University Graduate Fellowship, Stanford University (2000-2004)

Professional Education

  • Ph.D., Stanford University, Immunology (2006)
  • B.S., University of Victoria, Canada, Biochemistry and Microbiology (2000)

Research & Scholarship

Current Research and Scholarly Interests

Metastasis is a major clinical challenge driven by poorly understood cell state alterations. The goal of our lab is to use unbiased genomic methods and in vivo models to better understanding the molecular and cellular changes that underlie tumor progression and each step of the metastatic cascade. We use genetically-engineered mouse models of metastatic cancer in which the resulting tumors recapitulate the genetic alterations and histological progression of the human disease.

In these models, tumors develop within their appropriate microenvironment and undergo changes in their gene expression programs that endow them with the ability to invade blood and lymphatic vessels, survive in circulation, enter various distant organs, and ultimately grow into new tumor lesions. Given the dearth of human tissue samples from metastatic disease, especially from primary tumors and metastases from the same patient prior to therapy, these models represent a unique opportunity to understand the molecular biography of the most prevalent tumor types.

By generating activating and inactivating germline and inducible alleles, and modulating gene expression using lentiviral vectors, these models allow us to characterize the function of candidate genes and pathways during tumor progression and metastasis in vivo. By incorporating increasingly quantitative methods and powerful in vivo methods, our work is focused on uncovering general rules that govern tumor progression and metastatic spread and discovering novel therapeutic targets across the continuum of cancer progression including the lethal metastatic stage.


2013-14 Courses

Graduate and Fellowship Programs


Journal Articles

  • Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma GENES & DEVELOPMENT Li, C. M., Chen, G., Dayton, T. L., Kim-Kiselak, C., Hoersch, S., Whittaker, C. A., Bronson, R. T., Beer, D. G., Winslow, M. M., Jacks, T. 2013; 27 (14): 1557-1567


    Metastasis accounts for the vast majority of cancer-related deaths, yet the molecular mechanisms that drive metastatic spread remain poorly understood. Here we report that Tks5, which has been linked to the formation of proteolytic cellular protrusions known as invadopodia, undergoes an isoform switch during metastatic progression in a genetically engineered mouse model of lung adenocarcinoma. Nonmetastatic primary tumor-derived cells predominantly expressed a short isoform, Tks5short, while metastatic primary tumor- and metastasis-derived cells acquired increased expression of the full-length isoform Tks5long. This elevation of Tks5long to Tks5short ratio correlated with a commensurate increase in invadopodia activity in metastatic cells compared with nonmetastatic cells. Further characterization of these isoforms by knockdown and overexpression experiments demonstrated that Tks5long promoted invadopodia in vitro and increased metastasis in transplant models and an autochthonous model of lung adenocarcinoma. Conversely, Tks5short decreased invadopodia stability and proteolysis, acting as a natural dominant-negative inhibitor to Tks5long. Importantly, high Tks5long and low Tks5short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early stage patients. These data indicate that tipping the Tks5 isoform balance to a high Tks5long to Tks5short ratio promotes invadopodia-mediated invasion and metastasis.

    View details for DOI 10.1101/gad.222745.113

    View details for Web of Science ID 000322011500004

    View details for PubMedID 23873940

  • Response and Resistance to NF-kappa B Inhibitors in Mouse Models of Lung Adenocarcinoma CANCER DISCOVERY Xue, W., Meylan, E., Oliver, T. G., Feldser, D. M., Winslow, M. M., Bronson, R., Jacks, T. 2011; 1 (3): 236-247


    Lung adenocarcinoma is a leading cause of cancer death worldwide. We recently showed that genetic inhibition of the NF-?B pathway affects both the initiation and the maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this investigation, we tested the efficacy of small-molecule NF-?B inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-?B activity, the proteasome inhibitor bortezomib efficiently reduced nuclear p65, repressed NF-?B target genes, and rapidly induced apoptosis. Bortezomib also induced lung tumor regression and prolonged survival in tumor-bearing Kras(LSL-G12D/wt);p53(flox/flox) mice but not in Kras(LSL-G12D/wt) mice. After repeated treatment, initially sensitive lung tumors became resistant to bortezomib. A second NF-?B inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired resistance in mice. Our results using preclinical mouse models support the NF-?B pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma.Using small-molecule compounds that inhibit NF-?B activity, we provide evidence that NF-?B inhibition has therapeutic efficacy in the treatment of lung cancer. Our results also illustrate the value of mouse models in validating new drug targets in vivo and indicate that acquired chemoresistance may later influence bortezomib treatment in lung cancer.

    View details for DOI 10.1158/2159-8290.CD-11-0073

    View details for Web of Science ID 000295783300021

    View details for PubMedID 21874163

  • Nuclear factor I/B is an oncogene in small cell lung cancer GENES & DEVELOPMENT Dooley, A. L., Winslow, M. M., Chiang, D. Y., Banerji, S., Stransky, N., Dayton, T. L., Snyder, E. L., Senna, S., Whittaker, C. A., Bronson, R. T., Crowley, D., Barretina, J., Garraway, L., Meyerson, M., Jacks, T. 2011; 25 (14): 1470-1475


    Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed after it has metastasized. Despite the need to better understand this disease, SCLC remains poorly characterized at the molecular and genomic levels. Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC. We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC. Functional studies indicate that NFIB regulates cell viability and proliferation during transformation.

    View details for DOI 10.1101/gad.2046711

    View details for Web of Science ID 000292758200004

    View details for PubMedID 21764851

  • Suppression of lung adenocarcinoma progression by Nkx2-1 NATURE Winslow, M. M., Dayton, T. L., Verhaak, R. G., Kim-Kiselak, C., Snyder, E. L., Feldser, D. M., Hubbard, D. D., DuPage, M. J., Whittaker, C. A., Hoersch, S., Yoon, S., Crowley, D., Bronson, R. T., Chiang, D. Y., Meyerson, M., Jacks, T. 2011; 473 (7345): 101-U120


    Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 (also called Ttf-1 or Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically restricted chromatin regulator Hmga2. Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor.

    View details for DOI 10.1038/nature09881

    View details for Web of Science ID 000290218300039

    View details for PubMedID 21471965

  • Endogenous T Cell Responses to Antigens Expressed in Lung Adenocarcinomas Delay Malignant Tumor Progression CANCER CELL DuPage, M., Cheung, A. F., Mazumdar, C., Winslow, M. M., Bronson, R., Schmidt, L. M., Crowley, D., Chen, J., Jacks, T. 2011; 19 (1): 72-85


    Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here, we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors.

    View details for DOI 10.1016/j.ccr.2010.11.011

    View details for Web of Science ID 000287290300011

    View details for PubMedID 21251614

  • Stage-specific sensitivity to p53 restoration during lung cancer progression NATURE Feldser, D. M., Kostova, K. K., Winslow, M. M., Taylor, S. E., Cashman, C., Whittaker, C. A., Sanchez-Rivera, F. J., Resnick, R., Bronson, R., Hemann, M. T., Jacks, T. 2010; 468 (7323): 572-U249


    Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.

    View details for DOI 10.1038/nature09535

    View details for Web of Science ID 000284584200044

    View details for PubMedID 21107428

  • Selective role of calcineurin in haematopoiesis and lymphopoiesis EMBO REPORTS Gallo, E. M., Ho, L., Winslow, M. M., Staton, T. L., Crabtree, G. R. 2008; 9 (11): 1141-1148


    The calcineurin/NFAT (nuclear factor of activated T-cells) signalling pathway is essential for many aspects of vertebrate development and is the target of the widely used immunosuppressive drugs FK506 and cyclosporine A. The basis for the therapeutic specificity of these drugs has remained unclear, as calcineurin is expressed ubiquitously. By inactivating calcineurin during haematopoietic development, we found that although this signalling pathway has an important, non-redundant role in the regulation of lymphocyte developmental checkpoints, it is not essential for the development of blood myeloid lineages. These studies have shown that the specificity of calcineurin inhibitors arises from the selective use of calcineurin at distinct developmental stages. The requirement for calcineurin/NFAT in the development of the adaptive but not of the innate immune system is consistent with the idea that the evolutionary appearance of this pathway was involved in the emergence of vertebrates.

    View details for DOI 10.1038/embor.2008.174

    View details for Web of Science ID 000260586800017

    View details for PubMedID 18818667

  • Targeted deletion reveals essential and overlapping functions of the miR-17 similar to 92 family of miRNA clusters CELL Ventura, A., Young, A. G., Winslow, M. M., Lintault, L., Meissner, A., Erkeland, S. J., Newman, J., Bronson, R. T., Crowley, D., Stone, J. R., Jaenisch, R., Sharp, P. A., Jacks, T. 2008; 132 (5): 875-886


    miR-17 approximately 92, miR-106b approximately 25, and miR-106a approximately 363 belong to a family of highly conserved miRNA clusters. Amplification and overexpression of miR-1792 is observed in human cancers, and its oncogenic properties have been confirmed in a mouse model of B cell lymphoma. Here we show that mice deficient for miR-17 approximately 92 die shortly after birth with lung hypoplasia and a ventricular septal defect. The miR-17 approximately 92 cluster is also essential for B cell development. Absence of miR-17 approximately 92 leads to increased levels of the proapoptotic protein Bim and inhibits B cell development at the pro-B to pre-B transition. Furthermore, while ablation of miR-106b approximately 25 or miR-106a approximately 363 has no obvious phenotypic consequences, compound mutant embryos lacking both miR-106b approximately 25 and miR-17 approximately 92 die at midgestation. These results provide key insights into the physiologic functions of this family of microRNAs and suggest a link between the oncogenic properties of miR-17 approximately 92 and its functions during B lymphopoiesis and lung development.

    View details for DOI 10.1016/j.cell.2008.02.019

    View details for Web of Science ID 000253818000023

    View details for PubMedID 18329372

  • Calcineurin sets the bandwidth for discrimination of signals during thymocyte development NATURE Gallo, E. M., Winslow, M. M., Cante-Barrett, K., Radermacher, A. N., Ho, L., McGinnis, L., Iritani, B., Neilson, J. R., Crabtree, G. R. 2007; 450 (7170): 731-U11


    At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the alphabeta T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide-MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates.

    View details for DOI 10.1038/nature06305

    View details for Web of Science ID 000251209700056

    View details for PubMedID 18046413

  • Selective role of NFATc3 in positive selection of thymocytes JOURNAL OF IMMUNOLOGY Cante-Barrett, K., Winslow, M. M., Crabtree, G. R. 2007; 179 (1): 103-110


    The four Ca(2+)-dependent NFATc proteins are both signal transducers and transcription factors that reside in the cytoplasm until dephosphorylation by calcineurin. Dephosphorylation exposes nuclear import sequences and sends NFATc proteins into the nucleus where they assemble with nuclear partners into NFAT transcription complexes. Recent genetic studies have indicated that calcineurin-NFAT signaling is a major determinant of vertebrate morphogenesis and development. Mice lacking calcineurin activity show a complete block in positive selection of CD4 and CD8 double-positive thymocytes, yet the role of the NFATc proteins in T cell development has been controversial. In this study, we address the requirement for NFATc3 in T cell development by generating NFATc3 conditional knockout mice. We show that specific deletion of NFATc3 in thymocytes causes a partial block at the double-negative stage 3 and also a partial block in positive selection. Furthermore, the defect does not become more pronounced when NFATc2 is also absent, consistent with the fact that NFATc2-null mice do not have a T cell developmental defect. Expression of a nuclear (and constitutively active) NFATc1 even at subphysiological levels can rescue the transition of double-negative to double-positive thymocytes in RAG-null mice, but is unable to rescue development of CD4 and CD8 single-positive cells. In addition to NFATc3, this suggests a role for NFATc1 in T cell development. Our studies indicate that the signals that direct positive selection likely use both NFATc1 and NFATc3 downstream of calcineurin.

    View details for Web of Science ID 000247497600016

    View details for PubMedID 17579027

  • Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function NATURE Heit, J. J., Apelqvist, A. A., Gu, X., Winslow, M. M., Neilson, J. R., Crabtree, G. R., Kim, S. K. 2006; 443 (7109): 345-349


    The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in beta-cells in vivo are not understood. Here we show that mice with a beta-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, beta-cells lacking Cnb1 have a reduced expression of established regulators of beta-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient beta-cells rescues these defects and prevents diabetes. In normal adult beta-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases beta-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for beta-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark beta-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.

    View details for DOI 10.1038/nature05097

    View details for Web of Science ID 000240622000048

    View details for PubMedID 16988714

  • Calcineurin/NFAT signaling in osteoblasts regulates bone mass DEVELOPMENTAL CELL Winslow, M. M., Pan, M., Starbuck, M., Gallo, E. M., Deng, L., Karsenty, G., Crabtree, G. R. 2006; 10 (6): 771-782


    Development and repair of the vertebrate skeleton requires the precise coordination of bone-forming osteoblasts and bone-resorbing osteoclasts. In diseases such as osteoporosis, bone resorption dominates over bone formation, suggesting a failure to harmonize osteoclast and osteoblast function. Here, we show that mice expressing a constitutively nuclear NFATc1 variant (NFATc1(nuc)) in osteoblasts develop high bone mass. NFATc1(nuc) mice have massive osteoblast overgrowth, enhanced osteoblast proliferation, and coordinated changes in the expression of Wnt signaling components. In contrast, viable NFATc1-deficient mice have defects in skull bone formation in addition to impaired osteoclast development. NFATc1(nuc) mice have increased osteoclastogenesis despite normal levels of RANKL and OPG, indicating that an additional NFAT-regulated mechanism influences osteoclastogenesis in vivo. Calcineurin/NFATc signaling in osteoblasts controls the expression of chemoattractants that attract monocytic osteoclast precursors, thereby coupling bone formation and bone resorption. Our results indicate that NFATc1 regulates bone mass by functioning in both osteoblasts and osteoclasts.

    View details for DOI 10.1016/j.devcel.2006.04.006

    View details for Web of Science ID 000238244700011

    View details for PubMedID 16740479

  • NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21 NATURE Arron, J. R., Winslow, M. M., Polleri, A., Chang, C., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. 2006; 441 (7093): 595-600


    Trisomy 21 results in Down's syndrome, but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of Down's syndrome. Here we report that two genes, DSCR1 and DYRK1A , lie within the critical region of human chromosome 21 and act synergistically to prevent nuclear occupancy of NFATc transcription factors, which are regulators of vertebrate development. We use mathematical modelling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. Our observations of calcineurin-and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down's syndrome and human trisomy 21 are consistent with these predictions. We suggest that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's syndrome. More generally, these observations suggest that the destabilization of regulatory circuits can underlie human disease.

    View details for DOI 10.1038/nature04678

    View details for Web of Science ID 000237920800038

    View details for PubMedID 16554754

  • CD8(+) recent thymic emigrants home to and efficiently repopulate the small intestine epithelium NATURE IMMUNOLOGY Staton, T. L., Habtezion, A., Winslow, M. M., Sato, T., Love, P. E., Butcher, E. C. 2006; 7 (5): 482-488


    Prevailing knowledge dictates that naive alphabeta T cells require activation in lymphoid tissues before differentiating into effector or memory T cells capable of trafficking to nonlymphoid tissues. Here we demonstrate that CD8(+) recent thymic emigrants (RTEs) migrated directly into the small intestine. CCR9, CCL25 and alpha(4)beta(7) integrin were required for gut entry of CD8(+) RTEs. After T cell receptor stimulation, intestinal CD8(+) RTEs proliferated and acquired a surface phenotype resembling that of intraepithelial lymphocytes. CD8(+) RTEs efficiently populated the gut of lymphotoxin-alpha-deficient mice, which lack lymphoid organs. These studies challenge the present understanding of naive alphabeta T cell trafficking and suggest that RTEs may be involved in maintaining a diverse immune repertoire at mucosal surfaces.

    View details for DOI 10.1038/ni1319

    View details for Web of Science ID 000237008800013

    View details for PubMedID 16582913

  • The calcineurin phosphatase complex modulates immunogenic B cell responses IMMUNITY Winslow, M. M., Gallo, E. M., Neilson, J. R., Crabtree, G. R. 2006; 24 (2): 141-152


    A series of signal-directed transitions regulates the development of distinct populations of self-tolerant B cells and ultimately the production of antibody-producing plasma cells. We studied the role of calcineurin/NFAT signaling in B cells by deleting the regulatory b1 subunit of calcineurin specifically in B cells. Follicular (FO) and marginal zone (MZ) B cells develop normally in these mice, but B1 cell numbers are reduced. In vitro, calcineurin b1-deficient B cells have a cell-intrinsic proliferation defect downstream of the B cell receptor. These mice have higher total serum IgM despite the absence of B1 cells and have enhanced T cell-independent-1 responses. Conversely, mice with calcineurin b1-deficient B cells develop larger germinal centers and have reduced plasma cell development and antigen-specific antibody production during T cell-dependent immune responses. By several different criteria, calcineurin is dispensable for B cell tolerance, indicating that this phosphatase complex modulates immunogenic, but not tolerogenic, responses in vivo.

    View details for DOI 10.1016/j.immuni.2005.12.013

    View details for Web of Science ID 000235479000006

    View details for PubMedID 16473827

  • Calcineurin B1 is essential for positive but not negative selection during thymocyte development IMMUNITY Neilson, J. R., Winslow, M. M., Hur, E. M., Crabtree, G. R. 2004; 20 (3): 255-266


    During development, discrete cell fates often result from variation in the intensity of a particular signal. The mechanisms underlying these seemingly analog-to-digital switches are not understood. In developing T lymphocytes, low-intensity signals through the antigen receptor result in positive selection while more intense signals give rise to negative selection. By deleting the genetic locus encoding the regulatory B1 subunit of calcineurin specifically in thymocytes, we found an absolute requirement for calcineurin in positive selection. In contrast, calcineurin activity was dispensable in several models of negative selection. Unexpectedly, we found that removal of calcineurin activity from thymocytes results in inefficient ERK activation at the double-positive stage of thymocyte development, when selection occurs. These studies clarify the mechanism by which graded signals are converted to discrete outcomes in T cell development and further indicate that the developmental roles of calcineurin likely contribute to immunosuppression by calcineurin inhibitors.

    View details for Web of Science ID 000221442600004

    View details for PubMedID 15030770

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