Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848237 (acute stress)
 4,619 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA replication is tightly coordinated both with cell cycle cues and with responses to extracellular signals to maintain genome stability. We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2. Mutations that block normal cell cycle-regulated MAP kinase-mediated phosphorylation interfere with rapid Cdt1 reaccumulation at the end of S phase. Phosphomimetic mutations recapitulate the stabilizing effects of Cdt1 phosphorylation but also reduce the ability of Cdt1 to support origin licensing. Two other CRL4(Cdt2) targets, the cyclin-dependent kinase (CDK) inhibitor p21 and the methyltransferase PR-Set7/Set8, are similarly stabilized by MAP kinase activity. These findings support a model in which MAP kinase activity in G(2) promotes reaccumulation of a low-activity Cdt1 isoform after replication is complete.
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PMID:Stress-stimulated mitogen-activated protein kinases control the stability and activity of the Cdt1 DNA replication licensing factor. 2193 Jul 85

Data accumulating during the last two decades suggest that tumorigenesis is held in check by two major intrinsic failsafe mechanisms; apoptosis and cellular senescence. While apoptosis is a programmed cell death process, cellular senescence, which is the focus of this article, is defined as irreversible cell cycle arrest. This process is triggered either by telomere erosion or by acute stress signals including oncogenic stress induced by overactive oncogenes or underactive tumor suppressor genes. The outcome of this is often replication overload and oxidative stress resulting in DNA damage. Oncogenic stress induces at least three intrinsic pathways, p16/pRb-, Arf/p53/p21- and the DNA damage response (DDR)-pathways, that induce premature senescence if the stress exceeds a threshold level. Oncogene-induced senescence (OIS) is frequently observed in premalignant lesions both in animal tumor models and in human patients but is essentially absent in advanced cancers, suggesting that malignant tumor cells have found ways to bypass or escape senescence. This review focuses on cell-autonomous mechanism by which certain oncogenes, tumor suppressor genes and components of the DDR/DNA-repair machinery suppress senescence - mechanisms that are exploited by tumor cells to evade senescence and continue to multiply. In this way, tumor cells become addicted to the continuous activity of senescence suppressor proteins. However, some senescence pathways, although under suppression, may remain intact and can be re-established if senescence suppressor proteins are inactivated or if senescence inducers are reactivated. This can hopefully form the basis for a "pro-senescence therapy" strategy to combat cancer in the future.
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PMID:Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence. 2203 60