Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
Molecular and Cellular Biology (Impact Factor: 4.78). 04/2001; 21(5):1552-64. DOI: 10.1128/MCB.21.5.1552-1564.2001
Source: PubMed


The cellular function of p53 is complex. It is well known that p53 plays a key role in cellular response to DNA damage. Moreover,
p53 was implicated in cellular senescence, and it was demonstrated that p53 undergoes modification in senescent cells. However,
it is not known how these modifications affect the ability of senescent cells to respond to DNA damage. To address this question,
we studied the responses of cultured young and old normal diploid human fibroblasts to a variety of genotoxic stresses. Young
fibroblasts were able to undergo p53-dependent and p53-independent apoptosis. In contrast, senescent fibroblasts were unable
to undergo p53-dependent apoptosis, whereas p53-independent apoptosis was only slightly reduced. Interestingly, instead of
undergoing p53-dependent apoptosis, senescent fibroblasts underwent necrosis. Furthermore, we found that old cells were unable
to stabilize p53 in response to DNA damage. Exogenous expression or stabilization of p53 with proteasome inhibitors in old
fibroblasts restored their ability to undergo apoptosis. Our results suggest that stabilization of p53 in response to DNA
damage is impaired in old fibroblasts, resulting in induction of necrosis. The role of this phenomenon in normal aging and
anticancer therapy is discussed.

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Available from: Andrei Seluanov,
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    • "In some studies, p21 has been shown to play a role in cell survival through its cytoplasmic localization, rather than its nuclear localization associated with cell cycle arrest (Gartel and Tyner, 2002, Piccolo and Crispi 2012, Kreis et al. 2014). Interestingly, p21 has been reported to be a negative regulator of p53-mediated apoptosis (Gartel and Tyner, 2002), a known response reported in senescent fibroblasts (Seluanov et al. 2001). p21 has also been reported to promote cell survival in response to oxidative stress by integrating the DDR with endoplasmic reticulum (ER) stress signaling (Vitiello et al. 2009). "
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    ABSTRACT: Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a pro-inflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, well-established triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established “atypical” senescent states that may occur independent of DNA damage.
    Age 03/2015; DOI:10.1007/s11357-015-9764-2 · 3.45 Impact Factor
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    • "It should be noted that the inherent cellular stresses induced by AD, namely the elevated ROS production and DNA damage response, (Fig. 1E, F) are capable of inducing cell death. The fact that senescence is instead induced is likely dependent on the downstream stress pathways that are activated in response to AD [84], [85]. In this context, the ADIS-associated upregulation of pro-survival factors (Fig. 4A), downregulation of p53 (Fig. 2A) and the inability to induce downstream p53 effectors, such as Bax (Fig. 6B) serve to abrogate a cytotoxic response to AD and potentially promote persistence of cells that eventually resist ADIS and comprise androgen-refractory outgrowths. "
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    ABSTRACT: Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.
    PLoS ONE 06/2013; 8(6):e68003. DOI:10.1371/journal.pone.0068003 · 3.23 Impact Factor
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    • "Many cell types acquire resistance to apoptotic signals when they become senescent, possibly justifying both the stability of senescent cells in culture, and the accumulation of senescent cells with age [162] [163]. Moreover, manipulation of pro-and anti-apoptotic proteins can induce cells that are destined to die by apoptosis to enter the senescence pathway and vice versa [164] [165]. "
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    ABSTRACT: Ageing has been defined as the process of deterioration of many body functions over the lifespan of an individual. In spite of the number of different theories about ageing, there is a general consensus in identifying ageing effects in a reduced capacity to regenerate injured tissues or organs and an increased propensity to infections and cancer. In recent years the stem cell theory of ageing has gained much attention. Adult stem cells residing in mammalian tissues are essential for tissue homeostasis and repair throughout adult life. With advancing age, the highly regulated molecular signalling necessary to ensure proper cellular, tissue, and organ homeostasis loses coordination and leads, as a consequence, to a compromised potential of regeneration and repair of damaged cells and tissues. Although a complete comprehension of the molecular mechanisms involved in stem cell ageing and apoptosis is far to be reached, recent studies are beginning to unravel the processes involved in stem cell ageing, particularly in adult skeletal muscle stem cells, namely satellite cells. Thus, the focus of this review is to analyse the relationship between stem cell ageing and apoptosis with a peculiar attention to human satellite cells as compared to haematopoietic stem cells. Undoubtedly, the knowledge of age-related changes of stem cells will help in understanding the ageing process itself and will provide novel therapeutic challenges for improved tissue regeneration.
    Current pharmaceutical design 01/2012; 18(13):1694-717. DOI:10.2174/138161212799859657 · 3.45 Impact Factor
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