Two general concepts form the basis for our studies on the mechanisms of carcinogenesis. First is the concept that modulation in the phosphorylation of plasma membrane proteins serves a significant role in the process of neoplastic transformation. This concept is supported by our recent studies and by studies on oncogene products, such as pp60?src?. Second is the concept that carcinogenesis results from defects in the integrated control of cell proliferation and differentiation. This concept is also supported by our recent studies, by studies on normal and leukemic hematopoietic cells, and by studies on cells infected with viruses that express retroviral oncogene products. Our studies focus on experiments to determine how these two processes interface in mediating carcinogenesis. We will establish if modulation in plasma membrane phosphorylation influences the integrated control of cell proliferation and differentiation in normal cells and then determine if the initiation of carcinogenesis or complete transformation results from the development of defects in this regulatory process. These studies will employ """"""""normal"""""""" mesenchymal stem cells, clones of initiated mesenchymal stem cells and mesenchymal stem cells infected with temperature-sensitive oncogenic avian sarcoma virus. It is our hypothesis that, by determining if and how plasma membrane phosphoproteins influence the integrated control of normal and neoplastic stem cell proliferation and differentiation, we will acquire the necessary insights to design experiments to establish the mechanism by which these phosphoproteins mediate carcinogenesis. (A)

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cognition and Perception Study Section (CP)
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Mayo Clinic, Rochester
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Sparks, R L; Zschunke, M A; Seibel-Ross, E I et al. (1990) Specific expression of proteins and phosphoproteins in 3T3 T mesenchymal stem cells at distinct growth arrest and differentiation states. Cell Tissue Kinet 23:71-87
Filipak, M; Estervig, D N; Tzen, C Y et al. (1989) Integrated control of proliferation and differentiation of mesenchymal stem cells. Environ Health Perspect 80:117-25
Wier, M L; Scott, R E (1987) Polypeptide changes associated with loss of proliferative potential during the terminal event in differentiation. J Cell Biochem 33:137-50
Wier, M L; Scott, R E (1986) Aproliferin--a human plasma protein that induces the irreversible loss of proliferative potential associated with terminal differentiation. Am J Pathol 125:546-54
Pittelkow, M R; Scott, R E (1986) New techniques for the in vitro culture of human skin keratinocytes and perspectives on their use for grafting of patients with extensive burns. Mayo Clin Proc 61:771-7
Sparks, R L; Scott, R E (1986) Transforming growth factor type beta is a specific inhibitor of 3T3 T mesenchymal stem cell differentiation. Exp Cell Res 165:345-52
Pittelkow, M R; Wille Jr, J J; Scott, R E (1986) Two functionally distinct classes of growth arrest states in human prokeratinocytes that regulate clonogenic potential. J Invest Dermatol 86:410-7
Wille Jr, J J; Scott, R E (1986) Suppression of tumorigenicity by the cell-cycle-dependent control of cellular differentiation and proliferation. Int J Cancer 37:875-81
Wier, M L; Scott, R E (1986) Regulation of the terminal event in cellular differentiation: biological mechanisms of the loss of proliferative potential. J Cell Biol 102:1955-64
Scott, R E; Wille Jr, J J; Pittelkow, M R et al. (1985) Biological mechanisms of stem cell carcinogenesis: a concept for multiple phases in the initiation of carcinogenesis and the role of differentiation control defects. Carcinog Compr Surv 9:67-80

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