Role of p53 tumor suppressor in ageing: regulation of transient cell cycle arrest and terminal senescence.
In this study we investigated the function of p53 as a regulator of cell cycle progression in cycling and senescent cells. Using the conditional temperature-sensitive (ts) mutant we could prevent the detrimental effect of constitutive expression of high levels of wt p53 protein. High levels of wt p53 inhibited cell proliferation by blocking the cells to progress from G1 to S phase of the cell cycle. Flow cytometric analysis revelaed a maintenance of G1 cell population for a longer time depending on the prolonged expression of wt p53 protein. The p53 mediated inhibition of cell proliferation and of the cycle was reversible. However, a spontaneous increase of wt p53 occurring in ageing normal human MRC-5 fibroblasts was associated with irreversible reduction of proliferative potential. The accumulation of G1 cells was detected by flow cytometry. By the measurement of DNA content it is not possible to discriminate between cells arrested in G1 and G0 phase, therefore, the expression of G1 markers was determined. Analysis of the expression of distinct cell cycle regulators revealed that quiescent MRC-5 cells were in G0 phase. Our results indicate that cell cycle arrest occurring in senescent cells is associated with the G0 transition.
Wesierska-Gadek
J
J
Cell Cycle Regulation Group, Institute of Cancer Research, Vienna Medical University, Vienna, Austria. Jozefa.Gadek-Wesierski@meduniwien.ac.at
Wojciechowski
J
J
Ranftler
C
C
Schmid
G
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D006801:Humans; D051379:Mice; D051381:Rats; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*
D016159:Tumor Suppressor Protein p53