Our laboratory studies the role of platelet-derived growth factor (PDGF) in the regulation of connective tissue cell division. During the early stages of our work, we demonstrated that PDGF does not function alone to regulate cell division; rather, a second set of growth factors contained within the platelet-poor plasma fraction of blood functioned synergistically with PDGF for the optimum growth response. We showed that PDGF and the plasma growth factors (identified later as EGF and the insulin-like growth factors) control sequential events in the cell cycle termed, respectively, """"""""competence"""""""" and """"""""progression."""""""" Our early studies culminated in the first purification of PDGF to homogeneity in 1979. More recently, we have focused on the molecular action of PDGF. Using somatic cell fusion techniques, we demonstrated a transcription-dependent event in the mitogenic response to PDGF. Using recombinant DNA technology, we isolated and characterized a new family of """"""""competence genes"""""""" whose transcription is stimulated by PDGF. Epidermal growth factor, insulin, and platelet-poor plasma have either weak or an undetectable effect on transcription of these genes. Overshadowing all these observations was the finding that a pair of oncogenes (c-myc and C-fas) are contained within the competence gene family. Using DNA-mediated transfection, we showed that during the next five years, we intend to deal with an unexplored area in PDGF molecular biology-- namely the regulation of gene expression by PDGF. We hope to define a promoter element on the competence genes that mediates their coordinate induction. Moreover, we hope to determine how the signal is transduced from the PDGF receptor to the chromatin. (N)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA022042-09
Application #
3165698
Study Section
Molecular Biology Study Section (MBY)
Project Start
1977-08-01
Project End
1990-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Freter, R R; Alberta, J A; Hwang, G Y et al. (1996) Platelet-derived growth factor induction of the immediate-early gene MCP-1 is mediated by NF-kappaB and a 90-kDa phosphoprotein coactivator. J Biol Chem 271:17417-24
Guha, A; Dashner, K; Black, P M et al. (1995) Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 60:168-73
Freter, R R; Alberta, J A; Lam, K K et al. (1995) A new platelet-derived growth factor-regulated genomic element which binds a serine/threonine phosphoprotein mediates induction of the slow immediate-early gene MCP-1. Mol Cell Biol 15:315-25
Wang, C; Stiles, C D (1994) Platelet-derived growth factor alpha receptor gene expression: isolation and characterization of the promoter and upstream regulatory elements. Proc Natl Acad Sci U S A 91:7061-5
Alberta, J A; Rundell, K; Stiles, C D (1994) Identification of an activity that interacts with the 3'-untranslated region of c-myc mRNA and the role of its target sequence in mediating rapid mRNA degradation. J Biol Chem 269:4532-8
Freter, R R; Irminger, J C; Porter, J A et al. (1992) A novel 7-nucleotide motif located in 3' untranslated sequences of the immediate-early gene set mediates platelet-derived growth factor induction of the JE gene. Mol Cell Biol 12:5288-300
Hall, D J (1990) Regulation of c-myc transcription in vitro: dependence on the guanine-rich promoter element ME1a1. Oncogene 5:47-54
Oquendo, P; Alberta, J; Wen, D Z et al. (1989) The platelet-derived growth factor-inducible KC gene encodes a secretory protein related to platelet alpha-granule proteins. J Biol Chem 264:4133-7
Hall, D J; Stiles, C D (1987) Platelet-derived growth factor-inducible genes respond differentially to at least two distinct intracellular second messengers. J Biol Chem 262:15302-8
Zumstein, P; Stiles, C D (1987) Molecular cloning of gene sequences that are regulated by insulin-like growth factor I. J Biol Chem 262:11252-60

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