Expression of the wild-type p53 antioncogene induces guanine nucleotide-dependent stem cell division kinetics.

Abstract

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 ...

Mdm2-mediated ubiquitylation: p53 and beyond

“…Nevertheless, given the role of NUMB in binary cell fate decisions, this study suggests a role for p53 in the control of asymmetric cell division. Such a function for p53 has been suggested earlier 89 but this study may help revisit this important issue. The proposed model predicts that inactivation of the p53-Mdm2-NUMB axis, as the result of decreased NUMB expression for instance, may cause the skewing of stem cell division toward a symmetric pattern and thus favor tumor development.…”

Prostate Cancer Associated with p53 and Rb Deficiency Arises from the Stem/Progenitor Cell–Enriched Proximal Region of Prostatic Ducts

“…Furthermore, stem cell division kinetics could be induced by the up-regulation of p53 in differentiated cells (48,49). Further studies should directly establish the role of p53 and Rb in the prostate stem cell biology and determine if there is a common upstream regulator, similar to Bmi1, which coordinates the function of p53 and Rb pathways in prostate stem cells.…”

Ultraviolet A within Sunlight Induces Mutations in the Epidermal Basal Layer of Engineered Human Skin

“…Less efficient repair of UVA-induced genetic damage at the base 40 would also have this effect. Moreover, it might be possible that mutant p53 increases symmetric replication as wild-type p53 induces asymmetric stem-cell-like division, 41 and lead to rapid mutant p53 expansion at the basal epidermis. Chronic UVB exposure drives cells carrying mutant p53 to escape the stem cell compartment 42 to suprabasal layers, where the keratinocytes are still able to divide.…”