Proteasome inhibitors shorten replicative life span and induce a senescent-like phenotype of human fibroblasts

2006 ◽  
Vol 207 (3) ◽  
pp. 845-853 ◽  
Author(s):  
Claudio Torres ◽  
Lindsey Lewis ◽  
Vincent J. Cristofalo
Keyword(s):  
Life Span ◽  
Human Fibroblasts ◽  
Proteasome Inhibitors ◽  
Replicative Life Span

scholarly journals Control of Replicative Life Span in Human Cells: Barriers to Clonal Expansion Intermediate Between M1 Senescence and M2 Crisis

1999 ◽  
Vol 19 (4) ◽  
pp. 3103-3114 ◽  
Author(s):  
J. A. Bond ◽  
M. F. Haughton ◽  
J. M. Rowson ◽  
P. J. Smith ◽  
V. Gire ◽  
...  
Keyword(s):  
Life Span ◽  
Clonal Evolution ◽  
Human Fibroblasts ◽  
Fold Increase ◽  
Clonal Expansion ◽  
Suppressor Gene ◽  
Human Cells ◽  
Cell Type ◽  
Replicative Life Span ◽  
Population Doublings

ABSTRACT The accumulation of genetic abnormalities in a developing tumor is driven, at least in part, by the need to overcome inherent restraints on the replicative life span of human cells, two of which—senescence (M1) and crisis (M2)—have been well characterized. Here we describe additional barriers to clonal expansion (Mint) intermediate between M1 and M2, revealed by abrogation of tumor-suppressor gene (TSG) pathways by individual human papillomavirus type 16 (HPV16) proteins. In human fibroblasts, abrogation of p53 function by HPVE6 allowed escape from M1, followed up to 20 population doublings (PD) later by a second viable proliferation arrest state, MintE6, closely resembling M1. This occurred despite abrogation of p21WAF1 induction but was associated with and potentially mediated by a further ∼3-fold increase in p16INK4a expression compared to its level at M1. Expression of HPVE7, which targets pRb (and p21WAF1), also permitted clonal expansion, but this was limited predominantly by increasing cell death, resulting in a MintE7 phenotype similar to M2 but occurring after fewer PD. This was associated with, and at least partly due to, an increase in nuclear p53 content and activity, not seen in younger cells expressing E7. In a different cell type, thyroid epithelium, E7 also allowed clonal expansion terminating in a similar state to MintE7 in fibroblasts. In contrast, however, there was no evidence for a p53-regulated pathway; E6 was without effect, and the increases in p21WAF1 expression at M1 and MintE7 were p53 independent. These data provide a model for clonal evolution by successive TSG inactivation and suggest that cell type diversity in life span regulation may determine the pattern of gene mutation in the corresponding tumors.

scholarly journals Control of the Replicative Life Span of Human Fibroblasts by p16 and the Polycomb Protein Bmi-1

2003 ◽  
Vol 23 (1) ◽  
pp. 389-401 ◽  
Author(s):  
Koji Itahana ◽  
Ying Zou ◽  
Yoko Itahana ◽  
Jose-Luis Martinez ◽  
Christian Beausejour ◽  
...  
Keyword(s):  
Life Span ◽  
Replicative Senescence ◽  
Human Fibroblasts ◽  
Ring Finger ◽  
Dominant Negative ◽  
Life Span Extension ◽  
Replicative Life Span ◽  
Polycomb Protein ◽  
Human Fibroblast Strains ◽  
Dominant Negative Activity

ABSTRACT The polycomb protein Bmi-1 represses the INK4a locus, which encodes the tumor suppressors p16 and p14ARF. Here we report that Bmi-1 is downregulated when WI-38 human fibroblasts undergo replicative senescence, but not quiescence, and extends replicative life span when overexpressed. Life span extension by Bmi-1 required the pRb, but not p53, tumor suppressor protein. Deletion analysis showed that the RING finger and helix-turn-helix domains of Bmi-1 were required for life span extension and suppression of p16. Furthermore, a RING finger deletion mutant exhibited dominant negative activity, inducing p16 and premature senescence. Interestingly, presenescent cultures of some, but not all, human fibroblasts contained growth-arrested cells expressing high levels of p16 and apparently arrested by a p53- and telomere-independent mechanism. Bmi-1 selectively extended the life span of these cultures. Low O2 concentrations had no effect on p16 levels or life span extension by Bmi-1 but reduced expression of the p53 target, p21. We propose that some human fibroblast strains are more sensitive to stress-induced senescence and have both p16-dependent and p53/telomere-dependent pathways of senescence. Our data suggest that Bmi-1 extends the replicative life span of human fibroblasts by suppressing the p16-dependent senescence pathway.

Telomerase Alone Extends the Replicative Life Span of Human Skeletal Muscle Cells Without Compromising Genomic Stability

2003 ◽  
Vol 14 (15) ◽  
pp. 1473-1487 ◽  
Author(s):  
Martha Wootton ◽  
Karen Steeghs ◽  
Diana Watt ◽  
June Munro ◽  
Katrina Gordon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Life Span ◽  
Human Skeletal Muscle ◽  
Genomic Stability ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Replicative Life Span ◽  
Human Skeletal Muscle Cells

scholarly journals Loss of Ubp3 increases silencing, decreases unequal recombination in rDNA, and shortens the replicative life span in Saccharomyces cerevisiae

2014 ◽  
Vol 25 (12) ◽  
pp. 1916-1924 ◽  
Author(s):  
David Öling ◽  
Rehan Masoom ◽  
Kristian Kvint
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Rna Polymerase ◽  
Life Span ◽  
Rna Polymerase Ii ◽  
Ribosomal Dna ◽  
Genetic Evidence ◽  
Wild Type ◽  
Replicative Life Span ◽  
Unequal Recombination

Ubp3 is a conserved ubiquitin protease that acts as an antisilencing factor in MAT and telomeric regions. Here we show that ubp3∆ mutants also display increased silencing in ribosomal DNA (rDNA). Consistent with this, RNA polymerase II occupancy is lower in cells lacking Ubp3 than in wild-type cells in all heterochromatic regions. Moreover, in a ubp3∆ mutant, unequal recombination in rDNA is highly suppressed. We present genetic evidence that this effect on rDNA recombination, but not silencing, is entirely dependent on the silencing factor Sir2. Further, ubp3∆ sir2∆ mutants age prematurely at the same rate as sir2∆ mutants. Thus our data suggest that recombination negatively influences replicative life span more so than silencing. However, in ubp3∆ mutants, recombination is not a prerequisite for aging, since cells lacking Ubp3 have a shorter life span than isogenic wild-type cells. We discuss the data in view of different models on how silencing and unequal recombination affect replicative life span and the role of Ubp3 in these processes.

scholarly journals Stochastic Variation in Telomere Shortening Rate Causes Heterogeneity of Human Fibroblast Replicative Life Span

2004 ◽  
Vol 279 (17) ◽  
pp. 17826-17833 ◽  
Author(s):  
Carmen Martin-Ruiz ◽  
Gabriele Saretzki ◽  
Joanne Petrie ◽  
Juliane Ladhoff ◽  
Jessie Jeyapalan ◽  
...  
Keyword(s):  
Life Span ◽  
Human Fibroblast ◽  
Stochastic Variation ◽  
Telomere Shortening ◽  
Replicative Life Span ◽  
Shortening Rate

A comparison of the proliferative and replicative life span kinetics of cell cultures derived from monozygotic twins

In Vitro ◽  
1981 ◽  
Vol 17 (1) ◽  
pp. 20-27 ◽  
Author(s):  
J. M. Ryan ◽  
D. G. Ostrow ◽  
Xandra O. Breakefield ◽  
Elliot S. Gershon ◽  
Leo Upchurch
Keyword(s):  
Life Span ◽  
Cell Cultures ◽  
Monozygotic Twins ◽  
Replicative Life Span ◽  
Kinetics Of

Higher DNA repair activity is related with longer replicative life span in mammalian embryonic fibroblast cells

2011 ◽  
Vol 12 (6) ◽  
pp. 565-579 ◽  
Author(s):  
Seong-Hoon Park ◽  
Hong-Jun Kang ◽  
Hyun-Seok Kim ◽  
Min-Ju Kim ◽  
Jee-In Heo ◽  
...  
Keyword(s):  
Dna Repair ◽  
Life Span ◽  
Fibroblast Cells ◽  
Replicative Life Span ◽  
Repair Activity ◽  
Embryonic Fibroblast
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