Five years ago at the inception of this grant, we presented the hypothesis that the expression of defects in the integrated control of cellular differentiation and proliferation served a significant role in carcinogensis. To test this hypothesis we first initiated studies to establish how the integrated control of differentiation and proliferation is regulated in normal cells and what events mediate these processes. We next performed experiments to determine if and how the induction of carcinogenesis with chemical and/or physical agents abrogates the integrated control of cellular differentiation and proliferation. Excellent progress has been made in all these studies| We established that the integrated control of differentiation and proliferation is mediated at a distinct cell cycle arrest state, that a specific sequence of biological events must occur as part of this regulatory mechanism, and that this regulatory process is evident both in murine mesenchymal stem cells and in normal human epidermal cells. In addition, we have made significant progress in identifying and purifying physiological regulatory molecules from human blood that control these processes. We also established that physical and chemical agents that initiate carcinogenesis or cause complete carcinogenesis can induce stable defects in the integrated control of cellular differentiation and proliferation in mesenchymal stem cells and preliminary results suggest that comparable events occur in normal human epidermal cells. We therefore now propose to expand these studies with the specific goal to establish the mechanisms that regulate the integrated control of cellular differentiation and proliferation and the mechanisms by which carcinogenic agents disrupt these critical regulatory processes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA028240-07
Application #
3168044
Study Section
Pathology B Study Section (PTHB)
Project Start
1980-07-01
Project End
1991-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Schlager, J J; Hoerl, B J; Riebow, J et al. (1993) Increased NAD(P)H:(quinone-acceptor)oxidoreductase activity is associated with density-dependent growth inhibition of normal but not transformed cells. Cancer Res 53:1338-42
Wang, H; Scott, R E (1993) Inhibition of distinct steps in the adipocyte differentiation pathway in 3T3 T mesenchymal stem cells by dimethyl sulphoxide (DMSO). Cell Prolif 26:55-66
Scott, R E; Tzen, C Y; Witte, M M et al. (1993) Regulation of differentiation, proliferation and cancer suppressor activity. Int J Dev Biol 37:67-74
Wang, J Y; McCormack, S A; Viar, M J et al. (1993) Decreased expression of protooncogenes c-fos, c-myc, and c-jun following polyamine depletion in IEC-6 cells. Am J Physiol 265:G331-8
Hoerl, B J; Vroman, B T; Kasperbauer, J L et al. (1992) Biological characteristics of primary cultures of human gallbladder epithelial cells. Lab Invest 66:243-50
Witte, M M; Parker, R F; Wang, H et al. (1992) Repression of SV40 T oncoprotein expression by DMSO. J Cell Physiol 151:50-5
Wang, H; Scott, R E (1992) Induction of c-jun independent of PKC, pertussis toxin-sensitive G protein, and polyamines in quiescent SV40-transformed 3T3 T cells. Exp Cell Res 203:47-55
Blatti, S P; Scott, R E (1992) Stable induction of c-jun mRNA expression in normal human keratinocytes by agents that induce predifferentiation growth arrest. Cell Growth Differ 3:429-34
Keeting, P E; Scott, R E; Colvard, D S et al. (1992) Development and characterization of a rapidly proliferating, well-differentiated cell line derived from normal adult human osteoblast-like cells transfected with SV40 large T antigen. J Bone Miner Res 7:127-36
Keeting, P E; Scott, R E; Colvard, D S et al. (1991) Lack of a direct effect of estrogen on proliferation and differentiation of normal human osteoblast-like cells. J Bone Miner Res 6:297-304

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