Proliferation of normal cells is regulated at multiple points, any of which may be abnormal or absent in transformed cells. Thus study of normal cell growth is required to understand the mechanisms by which neoplastic cell escape growth control. The long-term objectives of this research are to understand how the proto-oncogenes c-myc and c-fos, which are associated with an early stage of cell proliferation in both lymphocytes and fibroblasts and whose viral counterparts are clearly implicated in neoplastic transformation, function in growth and activation of untransformed murine lymphocytes. Clonal murine T lymphocytes which respond to several growth-promoting signals in the absence of accessory cells will be used for these studies. myc and fos genes will be introduced into them using retroviral vectors by cocultivation with retrovirus-producing Psi-2 cells. Infected subclones constitutively expressing these oncogenes will be examined (1) for alterations in their growth responses to activating stimuli (Concanavalin A, clone-specific antibodies to the T cell receptor, Interleukin 2 (IL-2), the calcium ionophore A23187 plus phorbol myristate acetate), and (2) for expression of activation associated markers (IL-2 and IL-3 release, induction of IL-3 and Gamma-interferon genes, expression of cell-surface IL-2 receptors). In addition the inhibitors cyclosporin A and tetraethylammonium ion, which inhibit proliferation of the clones by acting at distinct points in the activation sequence, will be tested for whether they block induction of c-myc and c-fos in response to the growth-promoting stimuli listed above. If they do, they will be tested for whether their action is specific for lymphocytes, by determining whether they block induction of the same c-myc and c-fos genes in fibroblasts in response to the competence-inducing signals platelet-derived growth factor and phorbol myristate acetate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042471-02
Application #
3183854
Study Section
Immunobiology Study Section (IMB)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Martinez, Gustavo J; Pereira, Renata M; Äijö, Tarmo et al. (2015) The transcription factor NFAT promotes exhaustion of activated CD8? T cells. Immunity 42:265-278
Chen, Runqiang; Bélanger, Simon; Frederick, Megan A et al. (2014) In vivo RNA interference screens identify regulators of antiviral CD4(+) and CD8(+) T cell differentiation. Immunity 41:325-38
Carlson, Thaddeus J; Pellerin, Alex; Djuretic, Ivana M et al. (2014) Halofuginone-induced amino acid starvation regulates Stat3-dependent Th17 effector function and reduces established autoimmune inflammation. J Immunol 192:2167-76
Bandukwala, Hozefa S; Rao, Anjana (2013) 'Nurr'ishing Treg cells: Nr4a transcription factors control Foxp3 expression. Nat Immunol 14:201-3
Trifari, Sara; Pipkin, Matthew E; Bandukwala, Hozefa S et al. (2013) MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation. Proc Natl Acad Sci U S A 110:18608-13
Yigit, Erbay; Zhang, Quanwei; Xi, Liqun et al. (2013) High-resolution nucleosome mapping of targeted regions using BAC-based enrichment. Nucleic Acids Res 41:e87
Fogli, Laura K; Sundrud, Mark S; Goel, Swati et al. (2013) T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia. J Immunol 191:3100-11
Martinez, Gustavo J; Rao, Anjana (2012) Immunology. Cooperative transcription factor complexes in control. Science 338:891-2
Bandukwala, Hozefa S; Gagnon, John; Togher, Susan et al. (2012) Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc Natl Acad Sci U S A 109:14532-7
Benson, Micah J; Aijö, Tarmo; Chang, Xing et al. (2012) Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells. Proc Natl Acad Sci U S A 109:16252-7

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