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Cellular Senescence: Ex Vivo p53-Dependent Asymmetric Cell Kinetics.

Rambhatla L, Bohn SA, Stadler PB, Boyd JT, Coss RA, Sherley JL - J. Biomed. Biotechnol. (2001)

Bottom Line: 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.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.

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ABSTRACT
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.

No MeSH data available.


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Density-dependent p53 growth regulation reflects induction of linear population growth kinetics. (A), Linear growth by p53-expressing fibroblasts. Growth data for [19] as a function of the initial cell density of temperature-dependent (closed circles) and Zn-dependent times in (Figure 1). (B), Control cells. (C), p53-inducible cells. (D), Response of linear kinetics to p53 level induced by increasing Zn concentration [26]. The initial cell density ranged from 0.44 to 1.1 × 105 cells/ 25 cm2/5 ml. Two to six independent bars indicate the standard deviation.
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Figure 2: Density-dependent p53 growth regulation reflects induction of linear population growth kinetics. (A), Linear growth by p53-expressing fibroblasts. Growth data for [19] as a function of the initial cell density of temperature-dependent (closed circles) and Zn-dependent times in (Figure 1). (B), Control cells. (C), p53-inducible cells. (D), Response of linear kinetics to p53 level induced by increasing Zn concentration [26]. The initial cell density ranged from 0.44 to 1.1 × 105 cells/ 25 cm2/5 ml. Two to six independent bars indicate the standard deviation.

Mentions: Both types of p53-inducible cells exhibit a decrease in growthrate under conditions of p53 induction [25, 26, 27]. Underthe same conditions of temperature and Zn concentration, nosignificant growth effects occur for control cells. However, wenoted that characteristically this difference in the growthbetween control and p53-inducible cells did not occur at highcell density (Figure 1). The population doubling time (PDT) of control and p53-induced cells is in fact quite similaruntil cell density falls below about 5 × 104 cells per 25 cm2. Below this density, p53-specific growth suppression is manifest. The PDT of p53-induced cells increases 3-fold over a 4-fold range of decreased cell density (Figure 1, closed symbols). Over the same range, the PDT of control cells (Figure 1, open symbols) is essentially constant. This difference increases further at colony formation densities. At a density of 100 cells per 25 cm2, p53-inducible cells form colonies at 20 to 30 percent the efficiency of control cells [25, 26]. The ability of high cell density to prevent p53-dependent growth suppression is overcome by increased levels of p53 expression. This can be seen for Zn-dependent cultures initiated at the high cell density of 1 × 105 cells per 25 cm2. Whereas 60 μM Zn does not induce p53-dependent cell cycle arrest, 75 μM Zn, which induces a higher level of p53 protein, does so [26]; see also (Figure 2D).


Cellular Senescence: Ex Vivo p53-Dependent Asymmetric Cell Kinetics.

Rambhatla L, Bohn SA, Stadler PB, Boyd JT, Coss RA, Sherley JL - J. Biomed. Biotechnol. (2001)

Density-dependent p53 growth regulation reflects induction of linear population growth kinetics. (A), Linear growth by p53-expressing fibroblasts. Growth data for [19] as a function of the initial cell density of temperature-dependent (closed circles) and Zn-dependent times in (Figure 1). (B), Control cells. (C), p53-inducible cells. (D), Response of linear kinetics to p53 level induced by increasing Zn concentration [26]. The initial cell density ranged from 0.44 to 1.1 × 105 cells/ 25 cm2/5 ml. Two to six independent bars indicate the standard deviation.
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Related In: Results  -  Collection

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Figure 2: Density-dependent p53 growth regulation reflects induction of linear population growth kinetics. (A), Linear growth by p53-expressing fibroblasts. Growth data for [19] as a function of the initial cell density of temperature-dependent (closed circles) and Zn-dependent times in (Figure 1). (B), Control cells. (C), p53-inducible cells. (D), Response of linear kinetics to p53 level induced by increasing Zn concentration [26]. The initial cell density ranged from 0.44 to 1.1 × 105 cells/ 25 cm2/5 ml. Two to six independent bars indicate the standard deviation.
Mentions: Both types of p53-inducible cells exhibit a decrease in growthrate under conditions of p53 induction [25, 26, 27]. Underthe same conditions of temperature and Zn concentration, nosignificant growth effects occur for control cells. However, wenoted that characteristically this difference in the growthbetween control and p53-inducible cells did not occur at highcell density (Figure 1). The population doubling time (PDT) of control and p53-induced cells is in fact quite similaruntil cell density falls below about 5 × 104 cells per 25 cm2. Below this density, p53-specific growth suppression is manifest. The PDT of p53-induced cells increases 3-fold over a 4-fold range of decreased cell density (Figure 1, closed symbols). Over the same range, the PDT of control cells (Figure 1, open symbols) is essentially constant. This difference increases further at colony formation densities. At a density of 100 cells per 25 cm2, p53-inducible cells form colonies at 20 to 30 percent the efficiency of control cells [25, 26]. The ability of high cell density to prevent p53-dependent growth suppression is overcome by increased levels of p53 expression. This can be seen for Zn-dependent cultures initiated at the high cell density of 1 × 105 cells per 25 cm2. Whereas 60 μM Zn does not induce p53-dependent cell cycle arrest, 75 μM Zn, which induces a higher level of p53 protein, does so [26]; see also (Figure 2D).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus