The time-pattern of rises and falls in proliferation fades with senescence of mortal lines and is perpetuated in immortal rat hepatoma fao cell line |
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Authors: | J Maigné J Deschatrette S Sarrazin B Hecquet S Guerroui C Wolfrom |
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Institution: | 1. Unité de Recherche Génétique et mécanismes des maladies du foie de l’enfant, INSERM U347 H?pital de Bicêtre, 80 Rue du Général Leclerc, 94276, Kremlin-Bicêtre, France 2. Laboratoire de Pharmacodynamie Clinique, Centre Oscar Lambret, 59020, Lille Cedex, France
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Abstract: | Summary Immortal cells perpetuate the rises and falls of proliferation that are progressively damped in mortal long-term cultured
cells. For immortal rat hepatoma Fao cells, similar waves of proliferation occurred about every 3–4 wk. Under the same conditions,
embryonic human fibroblasts and transformed but not immortalized embryonic fibroblasts display similarly recurring proliferation
waves that progressively decrease in amplitude until senescence of the lines. In addition, strains of diploid normal human
skin fibroblasts cultured under different culture conditions display a similar time-pattern of proliferation. Although the
amplitude and baseline of these fluctuations are characteristic for each cell line, a common point was marked slow down in
proliferation after every sequence of about 25 population doublings for all cells. Renewed proliferation waves of Fao cells
allow about 22–23 additional population doublings each. Normal embryonic fibroblasts culture and its transformed counterpart
accumulate about 30 and 60 population doublings, respectively, before senescence. Normal fibroblast strains accumulate about
25 population doublings over their entire life spans. This halt in proliferation after every stretch of about 25 population
doublings may correspond to a structural or functional stop following attrition of telomeric DNA. This putative stop may be
bypassed once in transformed embryonic cells and repetitively in immortal cells. In support of this hypothesis, we observed
rapid telomere shortening, in two steps, during divisions of mortal embryonic cells, and maintenance of long telomeres in
immortal Fao cells, which may indicate episodic repair of telomeres. Alternatively, such maintenance of long telomeres may
reflect survival and successive clonal growth of rare cells with long telomeres. We suggest that the balance between telomere
attribution and repair processes regulates the waves of proliferation.
Equal contributors to these studies. |
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Keywords: | proliferation fluctuations cultured cells immortalization telomeres |
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