Loss of prohibitins, though it shortens the replicative life span of yeast cells undergoing division, does not shorten the chronological life span of G0-arrested cells

Piper, Peter W.; Bringloe, David

doi:10.1016/s0047-6374(01)00326-8

Cited by 28 publications

(19 citation statements)

References 30 publications

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“…While several nuclear and mitochondrial functions have been attributed to prohibitin in the past (21,62), recent studies also show that it might regulate cell surface functions, acting as a receptor for hitherto unknown ligands (26), and might regulate cell migration in collaboration with Raf-1 (44). A role for prohibitin in cellular senescence has been proposed for human fibroblasts and yeast (29,43). Studies of human fibroblasts correlated the decreased levels of prohibitin and passage numbers, leading to the hypothesis that prohibitin might be affecting senescence (10); no mechanistic studies were carried out on this observation.…”

Section: Discussionmentioning

confidence: 99%

Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes

Rastogi

Joshi

Dasgupta

et al. 2006

Molecular and Cellular Biology

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Prohibitin is a growth regulatory gene that has pleiotropic functions in the nucleus, mitochondria, and cytoplasmic compartments. Earlier studies had proposed a role for prohibitin in modulating cellular senescence, but the underlying mechanisms remain unknown. Here we show that senescence induced by DNAdamaging agents causes the localization of prohibitin to specific heterochromatic foci. Prohibitin could bind to heterochromatin protein 1 (HP1) family proteins and colocalized with HP1␥ in senescence-associated heterochromatic foci. Further, HP1␥ could synergize with prohibitin to repress E2F1-mediated transcriptional activity. The depletion of prohibitin by small interfering RNA or antisense techniques led to a reduction in the senescent phenotype, correlating with a reduced expression of senescence-associated ␤-galactosidase and fewer numbers of senescence-associated heterochromatic foci. Chromatin immunoprecipitation assays showed that prohibitin is needed for the recruitment of HP1␥ to E2F1-regulated proliferative promoters, leading to their repression. The ablation of prohibitin prevented the recruitment of HPI␥, but not Suv39H, to the promoters upon senescence. Prohibitin-mediated recruitment of HP1␥ occurred in only senescent cells, not in quiescent cells; thus, there is a dichotomy in the recruitment of different corepressors by prohibitin, depending on the type of growth arrest. These studies show that prohibitin plays a vital role in inducing cellular senescence.Primary mammalian cells in culture undergo a period of rapid proliferation; however, cell growth eventually decelerates and the cells enter a form of permanent cell cycle arrest termed senescence (20). While normal senescence limits the replicative potential of cells by telomere shortening (41), cells can undergo a similar permanent G 1 growth arrest in response to treatment with drugs like etoposide or adriamycin or in response to oncogenes like Ras (15,45,52,54,55). This growth arrest, also called STASIS (stress-or aberrant signaling-induced senescence), is similar to replicative senescence in that cells are unable to divide under mitotic stimulation even though they remain metabolically active. They also show changes in morphology that are typical of senescence (12,14,27). It has been shown that cultures of immortal cell lines can also undergo permanent cell cycle arrest in response to DNAdamaging agents, suggesting that senescence may act as a natural barrier to cancer progression (6,7,17,46,59,67).A senescent cell typically has a flattened morphology and increased granularity. At the biochemical level, senescence is accompanied by changes in metabolism and characterized by the induction of senescence-associated ␤-galactosidase activity (5, 13, 53), while at the genetic level, alterations in chromatin structure and gene expression patterns are observed (2,25,37,49,57). In senescing cells, the chromatin undergoes remodeling and senescence-associated heterochromatic foci (SAHF) can be detected (37). Heterochromatin is responsible for epigenet...

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Section: Discussionmentioning

confidence: 99%

Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes

Rastogi

Joshi

Dasgupta

et al. 2006

Molecular and Cellular Biology

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“…Of note, PHB promotes longevity in C. elegans, depending on metabolic status and genetic background [37], and PHB modulates insulin signaling in a phosphorylation-dependent manner [8,81]. Moreover, PHB has been reported to play a role in DNAdamaging agent-induced cellular senescence in MCF-7 and T47D breast carcinoma cell lines, by recruiting specific corepressors to inhibit E2F target genes [82], whereas loss of prohibitins in yeast shortens replicative lifespan [83]. In C. elegans, prohibitin deficiency shortens the lifespan of otherwise wild-type worms, while it dramatically extend the lifespan under compromised metabolic conditions, suggesting a context-dependent role of prohibitins, which has been linked to alterations in mitochondrial function and in fat metabolism [37,84].…”

Section: Box 1 Phb: a Potential Candidate In Integrating Metabolic Amentioning

confidence: 99%

Prohibitin in Adipose and Immune Functions

Ande

Nguyen

Nyomba

et al. 2016

Trends in Endocrinology & Metabolism

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“…Prohibitin deficiency induced by RNAi knockdown results in reduced lifespan in C. elegans and deletion of either prohibitin gene, PHB1 or PHB2 , shortens replicative lifespan in the budding yeast Saccharomyces cerevisiae (Artal-Sanz and Tavernarakis 2009; Coates and others 1997; Piper and Bringloe 2002; Piper and others 2002). A recent study showed that, in addition to shortening lifespan, prohibitin deficiency also causes enrichment of several UPR mt components in mitochondria of yeast cells and increased expression of the hsp-6 p ::gfp and hsp-60 p ::gfp reporters in worms (Schleit and others 2013).…”

Section: The Mitochondrial Unfolded Protein Response and Lifespan mentioning

confidence: 99%

The mitochondrial unfolded protein response and increased longevity: Cause, consequence, or correlation?

Bennett

Kaeberlein

2014

Experimental Gerontology

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The mitochondrial unfolded protein response is a conserved pathway that allows mitochondrial chaperones and other factors to be induced in response to mitochondrial dysfunction. Activation of this pathway has been proposed to underlie lifespan extension from knockdown or mutation of several nuclear encoded mitochondrial genes in Caenorhabditis elegans. In some cases, however, induction of the mitochondrial unfolded protein response is associated with a reduction of lifespan in both yeast and C. elegans. It also has yet to be demonstrated that induction of the mitochondrial unfolded protein response is sufficient to increase lifespan in the absence of overt mitochondrial dysfunction. In this perspective, we briefly review the evidence for and against a direct pro-longevity role of the mitochondrial unfolded protein response and suggest important areas of investigation for experimentally addressing this question.

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Loss of prohibitins, though it shortens the replicative life span of yeast cells undergoing division, does not shorten the chronological life span of G0-arrested cells

Cited by 28 publications

References 30 publications

Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes

Prohibitin Facilitates Cellular Senescence by Recruiting Specific Corepressors To Inhibit E2F Target Genes

Prohibitin in Adipose and Immune Functions

The mitochondrial unfolded protein response and increased longevity: Cause, consequence, or correlation?

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