Persistence of cell cycle times over many generations as determined by heritability of colony sizes of ras oncogene-transformed and non-transformed cells.

The persistence of cell lifetimes during about 10 successive cell generations was investigated by comparing the number of cells in primary colonies and in secondary colonies derived from primary colonies. Primary colonies were grown from single cells for 3 or 4 days (a time equivalent to an average of five cell generations) and the number of cells in each primary colony determined. Cells in each primary colony were dispersed to initiate secondary colonies, grown for the same time, and the number of cells in secondary colonies determined. Several criteria were used to compare primary and related secondary colonies, the most informative was found to be regression and correlation coefficients between number of cells in primary colonies and mean numbers of cells in related secondary colonies. For two non-transformed mouse fibroblast cell lines, NIH 3T3 and BALB 3T3, the regression and correlation coefficients of cell number in primary and secondary colonies were positive. This suggests inheritance of cell lifetimes over many cell generations. After the addition of an activated ras oncogene (human cellular Harvey ras, or viral Kirsten ras) some regression and correlation coefficients changed in magnitude but all remained positive. Comparison of experimental data and the results of computer simulations suggest that several models of inheritance of cell lifetimes are not adequate to explain the results, including a model of independence between lifetimes of mother and daughter cells and the common model that describes daughter cells as inheriting the lifetime of their mother with deviation. Simulations do suggest that cell lifetimes are inherited within clones as deviation from the lifetime of the initial cell, and that the ras oncogene does not destroy persistence within clones but does increase heterogeneity of cell lifetimes.