Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling

Lin, Athena W.; Barradas, Marta; Stone, James C.; Aelst, Linda Van; Serrano, Manuel; Lowe, Scott W.

doi:10.1101/gad.12.19.3008

Cited by 854 publications

(780 citation statements)

References 71 publications

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“…Erk is activated by its upstream kinases, MEK1 and MEK2 (Krepinsky et al, 2002). Activation of Erk is sufficient to transform NIH3T3 cells or mouse embryonic fibroblast (MEF) lacking either p53 or p16 (Cowley et al, 1994;Lin et al, 1998). However, Erk may also play a role in the cellular DNA damage response, which is a tumour suppression process.…”

Section: Introductionmentioning

confidence: 99%

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

Chen

Parihar

et al. 2005

Oncogene

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Although Erk kinase has been recently reported to function in the DNA damage response, the mechanism governing this process is unknown. We report here that hydroxyurea (HU) activates Erk via MEK1, a process that is sensitized by a constitutively active MEK1 (MEK1Q56P) and attenuated by a dominant-negative MEK1 (MEK1K97M). While ectopic MEK1Q56P sensitized HU-induced S-phase arrest, inhibition of Erk activation via U0126, PD98059, and MEK1K97M attenuated the arrest, and thereby enhanced cells to HU-induced toxicity. Taken together, we demonstrate an important contribution of Erk to the activation of the S-phase DNA damage checkpoint. This can be attributed to Erk's regulatory role in modulating ATR function. Inhibition of Erk activation with U0126/PD98059 and MEK1K97M substantially reduced HU-induced ATR nuclear foci, leading to a dramatic reduction of cH2AX and its nuclear foci. Reduction of MEK1 function by a small interference RNA (siRNA) MEK1 and ectopic MEK1K97M significantly decreased HU-induced cH2AX. Conversely, ectopic MEK1Q56P enhanced cH2AX foci. Furthermore, immunofluorescent and cell fractioning experiments revealed cytosolic and nuclear localization of ATR. HU treatment caused the redistribution of ATR from the cytosol to the nucleus, a process that is inhibited by U0126. Collectively, we show that Erk kinase modulates HU-initiated DNA damage response by regulating ATR function.

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Section: Introductionmentioning

confidence: 99%

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

Chen

Parihar

et al. 2005

Oncogene

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“…2 Indeed, besides the mitogenic response, MAPK can promote growth arrest, differentiation, replicative senescence, apoptosis, or resistance to radio-and chemotherapy. [3][4][5] Some of these events were shown to involve the p53 oncosuppressor. [4][5][6] In particular, constitutive Ras/MAPK signaling in primary human and murine fibroblasts activates p53 and induces premature senescence.…”

Section: Introductionmentioning

confidence: 99%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21 Waf1 , is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.

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“…Thus, it might be possible that Ras activates NF-kB to elevate cyclin D1 level, which then lead to an accelerated cell cycle progression of Ras transformed cells. However, since p21 waf/cip CDK inhibitor is also elevated by oncogenic Ras (Lin et al, 1998;Zhu et al, 1998), the overall growth control by Ras appears to be more complicated (Downward, 1997). In fact, the initial analysis of cell cycle regulatory proteins in RR/DN-IkBa-H cells revealed that both cyclin D1 and p21 waf/cip were elevated compared to RR-pBabe cells (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

“…The Ras proteins are important signaling molecules that regulate various cellular processes including growth, di erentiation, survival, and senescence (Downward, 1998;Kau man-Zeh et al, 1997;Khwaja et al, 1997;Lin et al, 1998;Lowy et al, 1993;Zhu et al, 1998). In response to external stimuli such as growth factors, Ras activates multiple downstream e ectors that initiate signaling cascades via activation of protein kinases (Lowy et al, 1993;White et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

NF-κB is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis

Zhang

et al. 2000

Oncogene

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Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling

Cited by 854 publications

References 71 publications

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

NF-κB is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis

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