The DNA Damage Signaling Pathway Connects Oncogenic Stress to Cellular Senescence

Mallette, Frédérick A.; Ferbeyre, Gerardo

doi:10.4161/cc.6.15.4516

Cited by 114 publications

(90 citation statements)

References 72 publications

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“…Recently, constitutive activation of DDR pathways, with the ensuing cellular senescence or cell death, has been identified as a biological barrier against activated oncogenes and tumor progression in early human lesions (Gorgoulis et al, 2005;Bartkova et al, 2005bBartkova et al, , 2006Di Micco et al, 2006;Malette and Ferbeyre 2007;Halazonetis et al, 2008). While oncogene-evoked replication stress was implicated in such DDR activation, and the concept validated for major types of human epithelial tumours (Gorgoulis et al, 2005;Bartkova et al, 2005bBartkova et al, , 2007Bartek et al, 2007), DDR activation was very low or absent in human testicular germ cell tumors (Bartkova et al, 2005a, and whether the DDR barrier operates in the pathogenesis of brain neoplasms remains to be studied.…”

Section: Introductionmentioning

confidence: 99%

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

et al. 2010

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Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low-and highgrade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n ¼ 41) and grade IV GBM (n ¼ 60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (cH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high-or lowoxygen culture conditions and in clinical specimens of both low-and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.

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Section: Introductionmentioning

confidence: 99%

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

et al. 2010

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“…A continuous activation of p53 and pocket proteins, and their pathways provokes the formation of senescence-associated DNA damage foci that are resistant to repair and enriched in g-H2AX and p53BP1. This common feature led to a new definition of senescence as a specific cell cycle arrest with persistent DNA damage signaling (Mallette and Ferbeyre, 2007). Senescent cells are viable but lose the ability to divide, change their phenotype and exhibit an altered gene expression profile.…”

Section: Introductionmentioning

confidence: 99%

Rb2/p130 is the dominating pocket protein in the p53–p21 DNA damage response pathway leading to senescence

et al. 2009

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The different pocket proteins are established as negative cell cycle regulators. With regard to the repressor functions of pocket proteins in cellular senescence, studies so far have mainly focused on pRb/p105. Here, we show that in a broad range of wild-type p53-expressing human tumor cells, and in human diploid fibroblasts, Rb2/p130 is the dominating pocket protein in replicative and in accelerated senescence. Senescent cells are arrested at the transition from late G1-to early S-phase, as indicated by the absence of S-and G2-phase cyclins A and B. Expression of cyclin A and entry into S-phase resumed after RNA interference-mediated knockdown of Rb2/ p130. Activation of different upstream pathways by overexpression of either p21 or p16 converged on Rb2/ p130 accumulation and induced senescence. In contrast, p53-or p21-negative cells treated with DNA-damaging agents failed to accumulate Rb2/p130 and to enter senescence. Our data suggest that Rb2/p130 is a member of the p53-p21 DNA damage signaling cascade, and represents the essential pocket protein family member needed for the induction of any type of senescence.

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“…In advanced cancers, this defense mechanism is bypassed by mutations in tumor suppressor genes (Courtois-Cox et al, 2008). Senescence is regulated by a complex signaling network and characterized by a persistent activation of the DNA damage signaling pathway (Mallette and Ferbeyre, 2007), chromatin remodeling through the formation of senescence-associated heterochromatin foci (SAHF) , and an increase of lysosomal b-galactosidase (b-gal) (Dimri and Campisi, 1994). Although SAHF help to maintain E2F targets in a repressed state, other mechanisms contribute to the overall inhibition of E2Fs in senescence.…”

Section: Introductionmentioning

confidence: 99%

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

et al. 2011

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The ADP-ribosylation factors (ARFs) 1 and 6 are small GTP-binding proteins, highly expressed and activated in several breast cancer cell lines and are associated with enhanced migration and invasiveness. In this study, we report that ARF1 has a critical role in cell proliferation. Depletion of this GTPase or expression of a dominant negative form, which both resulted in diminished ARF1 activity, led to sustained cell-growth arrest. This cellular response was associated with the induction of senescent markers in highly invasive breast cancer cells as well as in control mammary epithelial cells by a mechanism regulating retinoblastoma protein (pRB) function. When examining the role of ARF1, we found that this GTPase was highly activated in normal proliferative conditions, and that a limited amount could be found in the nucleus, associated with the chromatin of MDA-MB-231 cells. However, when cells were arrested in the G 0 /G 1 phase or transfected with a dominant negative form of ARF1, the total level of activated ARF1 was markedly reduced and the GTPase significantly enriched in the chromatin. Using biochemical approaches, we demonstrated that the GDP-bound form of ARF1 directly interacted with pRB, but not other members of this family of proteins. In addition, depletion of ARF1 or expression of ARF1T 31 N resulted in the constitutive association of pRB and E2F1, thereby stabilizing the interaction of E2F1 as well as pRB at endogenous sites of target gene promoters, preventing expression of E2F target genes, such as cyclin D1, Mcm6 and E2F1, important for cell-cycle progression. These novel findings provide direct physiological and molecular evidence for the role of ARF1 in controlling cell proliferation, dependent on its ability to regulate pRB/E2F1 activity and gene expression for enhanced proliferation and breast cancer progression.

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The DNA Damage Signaling Pathway Connects Oncogenic Stress to Cellular Senescence

Cited by 114 publications

References 72 publications

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

Rb2/p130 is the dominating pocket protein in the p53–p21 DNA damage response pathway leading to senescence

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

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