Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling

Satyanarayana, A.; Greenberg, Roger A.; Schaetzlein, Sonja; Buer, Jan; Masutomi, Kenkichi; Hahn, William C.; Zimmermann, Stefan; Martens, Uwe M.; Manns, Michael P.; Rudolph, K. Lenhard

doi:10.1128/mcb.24.12.5459-5474.2004

Cited by 77 publications

(45 citation statements)

References 64 publications

(109 reference statements)

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“…Our recent understanding of c-Myc's function as an integrator and regulator of metabolism, mass accumulation, and cell division would make it a prime candidate for such a surveillance function. Indeed, recent reports indicate that cell division makes cells more prone to senescence (19). To investigate the effects of a stress associated with aging on the Myc-Bmi-p16 circuit, we treated contactinhibited AG10770 cells with low, sublethal concentrations of the oxidant H 2 O 2 , and subsequently trypsinized and replated the cells at subconfluent density to promote cell-cycle entry.…”

Section: Resultsmentioning

confidence: 99%

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 ^INK4a

Guney

Sedivy

2006

Proc. Natl. Acad. Sci. U.S.A.

160

115

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Increased mitogenic signaling by positive effectors such as Ras or Myc can trigger senescence in normal cells, a response believed to function as a tumor-suppressive mechanism. We report here the existence of a checkpoint that monitors hypoproliferative signaling imbalances. Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16 INK4a . p16 INK4a expression was regulated by the Polycomb group repressor Bmi-1, which we show is a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a mechanism for the conversion of environmental inputs that converge on c-Myc into discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for limiting the proliferation of damaged or otherwise physiologically compromised cells would be expected to have important consequences on the generation of replicatively senescent cells during organismal aging.aging ͉ cellular senescence ͉ epigenetics ͉ signaling networks ͉ stress response

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Section: Resultsmentioning

confidence: 99%

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 ^INK4a

Guney

Sedivy

2006

Proc. Natl. Acad. Sci. U.S.A.

160

115

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“…The initial step of this DNA damage signalling is the formation of DNA damage foci at dysfunctional telomeres. These foci consist of proteins involved in DNA damage recognition and repair including γH2AX, 53bp1, NBS1, MDC1, among others (d' Adda di Fagagna et al, 2003;Satyanarayana et al, 2004). These DNA damage foci induce ATM/Chk2 and ATR/Chk1 kinase pathways (d' Adda di Fagagna et al, 2003) activating p53 (Gire et al, 2004, Chin et al, 1999 and its downstream target p21 (Brown et al, 1997)inducing cellular senescence (Brown et al, 1997).…”

Section: Dna Damage Signalling In Response To Telomere Dysfunctionmentioning

confidence: 99%

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Song¹,

Ju²,

Rudolph³

2009

Experimental Gerontology

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“…Furthermore, mitogenic stimulation promotes senescence (Satyanarayana et al, 2004;Takahashi et al, 2006). However, McMahon and colleagues previously showed that the high-level activation of the GFP-RAF1-ER kinase in serum-starved IMR-90 fibroblasts prevented DNA replication in these cells even after subsequent withdrawal of 4-HT in the presence of a serum-containing medium (Zhu et al, 1998).…”

Section: Raf-induced Senescence Of Serum-starved or Contact-inhibitedmentioning

confidence: 99%

Parallel pathways in RAF-induced senescence and conditions for its reversion

et al. 2011

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We developed a clonal WI-38hTERT/GFP-RAF1-ER immortal cell line to study RAF-induced senescence of human fibroblasts. Activation of the GFP-RAF1-ER kinase by addition of 4-hydroxy-tamoxifen led to a robust induction of senescence within one population doubling, accompanied by the assembly of heterochromatic foci. At least two pathways contribute in parallel to this senescence leading to the accumulation of p15, p16, p21 and p27 inhibitors of cyclin-dependent kinases (CKIs). Cells that traversed S phase after RAF1 kinase activation experienced a replicative stress manifested by phosphorylation of H2AX and Chk2 and synthesis of p21. However, about half the cells in the population were blocked without passing through S phase and did not show activation of DNA-damage checkpoints. When the cells were cultivated in 5% oxygen, RAF1 activation generated minimal reactive oxygen species, but RAF-induced senescence occurred efficiently in these conditions even in the presence of anti-oxidants or inhibitors of DNA checkpoint pathways. Despite the presence of heterochromatic foci, simultaneous knockdown of p16 and p21 with inactivation of the GFP-RAF1-ER kinase led to rapid reversion of the senescent state with the majority of cells becoming competent for long-term proliferation. These results demonstrate that replicative and oxidative stresses are not required for RAF-induced senescence, and this senescence is readily reversed upon loss of CKIs.

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Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling

Cited by 77 publications

References 64 publications

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 ^INK4a

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 ^INK4a

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Parallel pathways in RAF-induced senescence and conditions for its reversion

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Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling

Cited by 77 publications

References 64 publications

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 INK4a

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 INK4a

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Parallel pathways in RAF-induced senescence and conditions for its reversion

Contact Info

Product

Resources

About

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 ^INK4a

Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16 ^INK4a