The predominant type of cell division in adult mammals is renewal growth. Renewing stem cells in somatic tissues undergo continuous asymmetric divisions. One new daughter cell retains the division potential of the original stem cell, while the other differentiates into a functional constituent of the tissue. Disruptions of this process lead to the development of human cancers. We show that through a guanine nucleotide-dependent mechanism, the p53 antioncogene can induce exponentially dividing cells to switch to an asymmetric stem cell growth pattern. This finding suggests that the observed high frequency of p53 mutations in human cancers reflects a critical function in the regulation of somatic renewal growth.The p53 antioncogene has the distinction of being the most commonly altered genetic locus in examined human tumors (1,2). The high frequency of p53 gene alterations in diverse cancers suggests that the antioncogene plays a critical role in cellular processes that are fundamental to the development of human neoplasia. Recently, a number of hypotheses have been advanced for the cellular function of the p53 antioncogene (3-12). We have proposed a role for p53 in the regulation of guanine nucleotide biosynthesis. In our studies, regulation of the rate-limiting enzyme for guanine nucleotide biosynthesis, inosine 5'-monophosphate dehydrogenase (IMPD; IMP:NAD oxidoreductase, EC 1.1.1.205), by p53 expression can account for growth inhibition by the antioncogene (13).Our investigations of p53 function have been performed in cells that contain a stably integrated, conditional p53 expression system (13,14). C127, an immortal, nontumorigenic mouse mammary epithelial cell line, shown to express endogenous wild-type p53 protein (13), is the parent for the p53-inducible cells. When such cells are maintained at 37°C, the p53 transgene shows minimal expression. Culture at 32.5°C causes a 2-to 3-fold elevation in wild-type p53 protein concentration, a degree of induction within the physiologic range of p53 expression in C127 cells (13).In this report, we describe an investigation of changes in the growth properties of our experimental cell lines in response to elevated p53 expression. We find that increased p53 expression induces a switch from exponential growth kinetics to division kinetics similar to those of renewing stem cells in vivo. In addition, we found that primary human cells of both fibroblast and epithelial origin exhibit similar, though not quantitatively identical, properties. Guanine nucleotide precursors, which rescue cells from p53-induced growth inhibition (13), prevent the switch to renewal growth kinetics. The described studies functionally link stem cell renewal and guanine nucleotide metabolism to one another and to the expression of p53. This relationship can account for many features of p53 gene exThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate ...

Although senescence is a defining property of euploid mammalian cells, its physiologic basis remains obscure. Previously, cell kinetics properties of normal tissue cells have not been considered in models for senescence. We now provide evidence that senescence is in fact the natural consequence of normal in vivo somatic stem cell kinetics extended in culture. This concept of senescence is based on our discovery that cells engineered to conditionally express the well-recognized tumor suppressor protein and senescence factor, p53, exhibit asymmetric cell kinetics. In vivo, asymmetric cell kinetics are essential for maintenance of somatic stem cells; ex vivo, the same cell kinetics yield senescence as a simple kinetic endpoint. This new “asymmetric cell kinetics model” for senescence suggests novel strategies for the isolation and propagation of somatic tissue stem cells in culture.

The application of the exponential growth equation is the standard method employed in the quantitative analyses of mammalian cell proliferation in culture. This method is based on the implicit assumption that, within a cell population under study, all division events give rise to daughter cells that always divide. When a cell population does not adhere to this assumption, use of the exponential growth equation leads to errors in the determination of both population doubling time and cell generation time. We have derived a more general growth equation that defines cell growth in terms of the dividing fraction of daughter cells. This equation can account for population growth kinetics that derive from the generation of both dividing and non-dividing cells. As such, it provides a sensitive method for detecting non-exponential division dynamics. In addition, this equation can be used to determine when it is appropriate to use the standard exponential growth equation for the estimation of doubling time and generation time.