Normal human cells in vitro exhibit a stringent limitation of division capacity in contract to tumor-derived and virus-, carcinogen- or irradiation-transformed cells that can divide indefinitely (immortal). We do not yet understand the mechanisms that limit the division potential of normal human cells or the changes occurring to yield immortal cells. What we have found is that the immortal phenotype results from recessive changes in normal cell growth control and that there are multiple ways by which cells can become immortal. In this study we propose to systematically separate a variety of immortal human cell lines into complementation groups which, when fused with each other, yield hybrids having limited division potential. The number of complementation groups into which immortal cells can be assigned will give an estimation of the number of control processes present in the normal cell that can be modified to result in uncontrolled cell division. The experiments are also designed to demonstrate the effect, if any, of cell derivation, type of tumor, inducer of immortality and presence of active oncogenes on the assignment of complementation group. In addition, they will demonstrate changes in cellular proto-oncongene expression as hybrids divide and cease division and in the variant immortal cells that arise in non-dividing hybrid populations. The results should be of intrinsic interest to investigators studying various aspects of growth control. Furthermore, they will allow us, in the future, to take a directed approach to the study of the molecular basis of immortalization. Cell lines representative of each complementation group can be analyzed to determine what recessive changes have occurred in normal cell growth control to result in immortality in each case, rather than study randomly selected immortal cell lines.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG005333-03
Application #
3115909
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1985-05-01
Project End
1988-04-30
Budget Start
1987-05-01
Budget End
1988-04-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Porter, M B; Pereira-Smith, O M; Smith, J R (1992) Common senescent cell-specific antibody epitopes on fibronectin in species and cells of varied origin. J Cell Physiol 150:545-51
Smith, J R; Ning, Y; Pereira-Smith, O M (1992) Why are transformed cells immortal? Is the process reversible? Am J Clin Nutr 55:1215S-1221S
Pereira-Smith, O M; Ning, Y (1992) Molecular genetic studies of cellular senescence. Exp Gerontol 27:519-22
Ning, Y; Pereira-Smith, O M (1991) Molecular genetic approaches to the study of cellular senescence. Mutat Res 256:303-10
Stein, G H; Drullinger, L F; Robetorye, R S et al. (1991) Senescent cells fail to express cdc2, cycA, and cycB in response to mitogen stimulation. Proc Natl Acad Sci U S A 88:11012-6
Ning, Y; Shay, J W; Lovell, M et al. (1991) Tumor suppression by chromosome 11 is not due to cellular senescence. Exp Cell Res 192:220-6
Shay, J W; Pereira-Smith, O M; Wright, W E (1991) A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 196:33-9
Ning, Y; Weber, J L; Killary, A M et al. (1991) Genetic analysis of indefinite division in human cells: evidence for a cell senescence-related gene(s) on human chromosome 4. Proc Natl Acad Sci U S A 88:5635-9
Spiering, A L; Pereira-Smith, O M; Smith, J R (1991) Correlation between complementation group for immortality and DNA synthesis inhibitors. Exp Cell Res 195:541-5
Pereira-Smith, O M; Robetorye, S; Ning, Y et al. (1990) Hybrids from fusion of normal human T lymphocytes with immortal human cells exhibit limited life span. J Cell Physiol 144:546-9

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