Receptor and cytoplasmic tyrosine kinases trigger signaling through common pathways in which lie other critical regulators of cell growth. Together, these signal transducers govern the response to extracellular mitogens which drive progression through the G1 phase of the cell cycle. Critical rate limiting regulators of G1 progression include MYC, the D-and E-type G1 cyclins, and their catalytic cyclin-dependent kinase (CDK) partners. NIH3T3 fibroblasts expressing a mutant human colony-stimulating factor-1 receptor [CSF-1R (Y809F)] exhibit attenuated receptor kinase activity in response to CSF-1 and fail to proliferate when stimulated with the growth factor. These CSF-1 stimulated cells remain viable and undergo induction of various immediate early response genes, such as FOS and Jun family members, but they do not manifest MYC, cyclin D or E induction, and they remain arrested in early G1 phase. Rescue of the receptor defect has identified common signal transducers, including MYC itself, ETS factors, and the D-type cyclins, that act as essential downstream components required for S phase entry. We will utilize an unbiased approach to identify essential components of signaling pathways that functionally connect CSF-1 induced mitogenic signals to MYC and cyclin D function. Cells expressing CSF-1R[Y809F] will be infected with retroviruses encoding mammalian cDNA libraries, and those cDNAs that specify proteins able to conditionally rescue mitogenicity in response to CSF- 1 will be identified. Selected genes will be studied for their ability to induce MYC expression or to bypass its functions. Many positive regulators of G1 progression (including CSF-1R, MYC, and cyclin D1) can function as collaborating oncogenes when mutated or constitutively overexpressed, whereas their opposing negative regulators function as tumor suppressors. We therefore anticipate that newly identified transducers of mitogenic signals identified here will similarly be implicated in oncogenesis when genetically altered or inappropriately expressed. The identification of novel effector molecules should enable definition of regulatory networks that govern events late in G1 phase, including the commitment to enter S phase.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA056819-09
Application #
6150119
Study Section
Pathology B Study Section (PTHB)
Program Officer
Spalholz, Barbara A
Project Start
1992-06-12
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
9
Fiscal Year
2000
Total Cost
$292,471
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Eischen, C M; Roussel, M F; Korsmeyer, S J et al. (2001) Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol 21:7653-62
Randle, D H; Zindy, F; Sherr, C J et al. (2001) Differential effects of p19(Arf) and p16(Ink4a) loss on senescence of murine bone marrow-derived preB cells and macrophages. Proc Natl Acad Sci U S A 98:9654-9
Dervieux, T; Blanco, J G; Krynetski, E Y et al. (2001) Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res 61:5810-6
Eischen, C M; Woo, D; Roussel, M F et al. (2001) Apoptosis triggered by Myc-induced suppression of Bcl-X(L) or Bcl-2 is bypassed during lymphomagenesis. Mol Cell Biol 21:5063-70
Sasaki, K; Taura, F; Shoyama, Y et al. (2000) Molecular characterization of a novel beta-glucuronidase from Scutellaria baicalensis georgi. J Biol Chem 275:27466-72
Groth, A; Weber, J D; Willumsen, B M et al. (2000) Oncogenic Ras induces p19ARF and growth arrest in mouse embryo fibroblasts lacking p21Cip1 and p27Kip1 without activating cyclin D-dependent kinases. J Biol Chem 275:27473-80
Lam, P Y; Sublett, J E; Hollenbach, A D et al. (1999) The oncogenic potential of the Pax3-FKHR fusion protein requires the Pax3 homeodomain recognition helix but not the Pax3 paired-box DNA binding domain. Mol Cell Biol 19:594-601
Inoue, K; Roussel, M F; Sherr, C J (1999) Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. Proc Natl Acad Sci U S A 96:3993-8
Sexl, V; Diehl, J A; Sherr, C J et al. (1999) A rate limiting function of cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2. Oncogene 18:573-82
Eischen, C M; Weber, J D; Roussel, M F et al. (1999) Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13:2658-69

Showing the most recent 10 out of 32 publications