Loss of HuR Is Linked to Reduced Expression of Proliferative Genes during Replicative Senescence

Wang, Wengong; Yang, Xiaoling; Cristofalo, Vincent J.; Holbrook, Nikki J.; Gorospe, Myriam

doi:10.1128/mcb.21.17.5889-5898.2001

Cited by 168 publications

(189 citation statements)

References 39 publications

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“…HuR decreases dramatically as cells age and reach senescence (Wang et al, 2001) and this leads to a destabilization of SIRT1 mRNA (Abdelmohsen et al, 2007). High levels of SIRT1 and HuR contribute to the enhanced survival of rapidly proliferating cells after oxidative damage, as opposed to senescent cells that are more sensitive to oxidative damage (Abdelmohsen et al, 2007).…”

Section: Regulation Of Sirt1 Expression In Primary Cells and Its Overmentioning

confidence: 99%

Sirtuins: critical regulators at the crossroads between cancer and aging

2007

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Sirtuins (SIRTs 1À7), or class III histone deacetylases (HDACs), are protein deacetylases/ADP ribosyltransferases that target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SIRT1, -2, -3 and -5) or ADP ribosylation (SIRT4 and -6). The orthologs of sirtuins in lower organisms play a critical role in regulating lifespan. As cancer is a disease of aging, we discuss the growing implications of the sirtuins in protecting against cancer development. Sirtuins regulate the cellular responses to stress and ensure that damaged DNA is not propagated and that mutations do not accumulate. SIRT1 also promotes replicative senescence under conditions of chronic stress. By participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers. Here, we review the growing implications of sirtuins both in cancer prevention and as specific and novel cancer therapeutic targets.

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Section: Regulation Of Sirt1 Expression In Primary Cells and Its Overmentioning

confidence: 99%

Sirtuins: critical regulators at the crossroads between cancer and aging

2007

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“…CR 3′UTR p16 mRNA turnover during replicative senescence W. Wang et al and p21, and reduced levels of cyclin A, cyclin B1 and c-fos (Fig 1A;Wang et al, 2001). Given the presence of a distinct ARE in the p16 mRNA (Fig 1B), we postulated that its senescence-dependent expression might be influenced by changes in mRNA stability.…”

Section: ′Utrmentioning

confidence: 99%

“…The involvement of mRNA turnover was reported for transcripts encoding cyclins A and B1, which were shown to be targets of binding and stabilization by the RNA-binding protein (RBP) HuR during the proliferative phases of the cell division cycle and in early-passage HDFs (Wang et al, 2000b(Wang et al, , 2001). The 3 0 -untranslated regions (UTRs) of mRNAs encoding cyclins A and B1 contain A þ U-rich elements (AREs), the best-understood cis-acting determinants of transcript stability (Xu et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, comparisons of young (Y) and senescent respectively), showed that the senescent populations had considerably lower CDK activity, diminished rates of [ 3 H]thymidine incorporation, increased G1-phase cells and greatly elevated activity of a neutral, senescence-associated b-galactosidase (SA-b-gal) that is used as a biomarker of replicative senescence (Dimri et al, 1995;Wang et al, 2001). In addition, senescent cells exhibited higher levels of cyclin D1 …”

Section: Introductionmentioning

confidence: 99%

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Increased stability of the p16 mRNA with replicative senescence

et al. 2005

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Expression of p16 INK4a is elevated during ageing and replicative senescence. Here, we report the presence of an instability determinant within the 3 0 -untranslated region (UTR) of the p16 messenger RNA in WI-38 human diploid fibroblasts. The p16 3 0 UTR was found to be a specific target of AUF1, an RNAbinding protein implicated in promoting mRNA decay. Both AUF1 levels and AUF1-p16 mRNA associations were strikingly more abundant in early-passage than late-passage fibroblast cultures. Moreover, short interfering RNA-based reductions in AUF1 levels increased the stability of p16 3 0 UTR-containing transcripts, elevated the expression of p16 and accentuated the senescence phenotype. Together, our findings show that p16 mRNA turnover decreases during replicative senescence and that the instability-conferring region is located within the 3 0 UTR of p16, as well as identifying AUF1 as a critical mediator of these regulatory events.

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“…While the hypothesis that HuR exports target mRNAs to the cytoplasm awaits experimental demonstration, HuR's influence on target mRNA stabilization and translation is robustly linked to its cytoplasmic presence. Through its post-transcriptional effects on target mRNAs (such as those encoding cyclin A, cyclin B1, cfos, VEGF, TNF-a, b-catenin, c-myc, cyclooxygenase-2, myogenin, MyoD, GM-CSF, interleukins, p21, p27, p53, and hsp70), cytoplasmic HuR is emerging as a major regulator of various cellular responses, including cell division, carcinogenesis, muscle cell differentiation, replicative senescence, immune cell activation, and the stress response (Atasoy et al, 1998;Wang et al, 2000bWang et al, , 2001Kullmann et al, 2002;Figueroa et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs

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Mazan-Mamczarz

Kawai

et al. 2004

EMBO J

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RNA-binding proteins HuR and AUF1 bind to many common AU-rich target mRNAs and exert opposing influence on target mRNA stability, but the functional interactions between HuR and AUF1 have not been systematically studied. Here, using common target RNAs encoding p21 and cyclin D1, we provide evidence that HuR and AUF1 can bind target transcripts on both distinct, nonoverlapping sites, and on common sites in a competitive fashion. In the nucleus, both proteins were found together within stable ribonucleoprotein complexes; in the cytoplasm, HuR and AUF1 were found to bind to target mRNAs individually, HuR colocalizing with the translational apparatus and AUF1 with the exosome. Our results indicate that the composition and fate (stability, translation) of HuR- and/or AUF1-containing ribonucleoprotein complexes depend on the target mRNA of interest, RNA-binding protein abundance, stress condition, and subcellular compartment

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Loss of HuR Is Linked to Reduced Expression of Proliferative Genes during Replicative Senescence

Cited by 168 publications

References 39 publications

Sirtuins: critical regulators at the crossroads between cancer and aging

Sirtuins: critical regulators at the crossroads between cancer and aging

Increased stability of the p16 mRNA with replicative senescence

Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs

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