DNA-damage inducible genes

Papathanasiou, Matilda; Fornace, Albert J.

doi:10.1007/978-1-4615-3872-1_2

Cited by 14 publications

(7 citation statements)

References 61 publications

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“…[1][2][3] It is reported that high frequency point mutations are found in exon 4 of Gadd45a in human pancreatic cancer and the expression level of Gadd45a, combined with p53 status, significantly affects the survival of patients. 4 There is also evidence to show Gadd45a as an abnormally methylated gene in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Gadd45a inhibits cell migration and invasion by altering the global RNA expression

Shan

Zhan

et al. 2012

Cancer Biology & Therapy

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Section: Introductionmentioning

confidence: 99%

Gadd45a inhibits cell migration and invasion by altering the global RNA expression

Shan

Zhan

et al. 2012

Cancer Biology & Therapy

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“…GADD45 can be rapidly induced by various types of stresses, e.g., UV irradiation (17), and its overexpression in various types of tumor cells causes an inhibition of cell growth (18). p21 cip1 causes an inhibition of cdks (e.g., cdk4 and cdk6) in many types of cells, including ECs (19,20).…”

mentioning

confidence: 99%

Molecular mechanism of endothelial growth arrest by laminar shear stress

Lin

Hsu

Chen

et al. 2000

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

233

172

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This study was designed to elucidate the mechanism underlying the inhibition of endothelial cell growth by laminar shear stress. Tumor suppressor gene p53 was increased in bovine aortic endothelial cells subjected to 24 h of laminar shear stress at 3 dynes (1 dyne ‫؍‬ 10 N)͞cm 2 or higher, but not at 1.5 dynes͞cm 2 . One of the mechanisms of the shear-induced increase in p53 is its stabilization after phosphorylation by c-Jun N-terminal kinase. To investigate the consequence of the shear-induced p53 response, we found that prolonged laminar shear stress caused increases of the growth arrest proteins GADD45 (growth arrest and DNA damage inducible protein 45) and p21 cip1 , as well as a decrease in phosphorylation of the retinoblastoma gene product. Our results suggest that prolonged laminar shear stress causes a sustained p53 activation, which induces the up-regulation of GADD45 and p21 cip1 . The resulting inhibition of cyclin-dependent kinase and hypophosphorylation of retinoblastoma protein lead to endothelial cell cycle arrest. This inhibition of endothelial cell proliferation by laminar shear stress may serve an important homeostatic function by preventing atherogenesis in the straight part of the arterial tree that is constantly subjected to high levels of laminar shearing. H emodynamic forces regulate the structure and function of the blood vessel wall (1, 2). Vascular endothelial cells (ECs), located at the interface between the circulating blood and the blood vessel, are exposed to shear stresses resulting from the tangential forces exerted by the flowing fluid on the vessel wall. The magnitude and pattern of the shear stress acting on ECs depend on blood flow, blood viscosity, and the vascular geometry, which varies with the location in the vascular tree. In regions of the vascular tree that have predilection for atherosclerotic lesions (e.g., branch points of large to medium arteries), the complex flow pattern is associated with low shear stresses that exhibit large spatial variations. In contrast, in the straight parts of the arterial tree, which are generally spared from atherosclerosis, blood flow is more laminar, and the high level of shear stress shows little spatial variations. Previous in vitro and in vivo findings have shown that ECs respond to shear stress in a magnitude-and flow pattern-dependent manner (3-5). ECs subjected to a long duration of laminar shear stress at the relatively high levels seen in the straight part of the arterial tree [i.e., on the order of 10-20 dynes (1 dyne ϭ 10 N)͞cm 2 ] have been found to have a lower rate of DNA synthesis than that under static condition (6). This shear-induced reduction of DNA synthesis, which indicates a decrease in cell proliferation, is not seen in ECs subjected to low shear stresses at 1-5 dynes͞cm 2 (6-8). The molecular mechanisms by which EC growth is regulated by the high level of sustained laminar shear stress seen in the lesion-resistant part of the arterial tree have not yet been clearly established. The elucidation of these mechanisms...

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“…Sources of DNA-damaging agents can be endogenous, such as free radicals and peroxides generated during normal metabolic processes or inflammation, or they can be exogenous, such as the myriad potentially damaging chemical and physical agents in the environment, either inadvertently or therapeutically in the case of cancer treatment. One way by which eukaryotic organisms are able to respond to this type of genotoxic stress is by transiently arresting cell-cycle progression from GI into S and from G2 into M (Weinert and Hartwell, 1990;Kaufmann et at., 1991;Papathanasiou and Fornace, 1991;O'Connor et al, 1992). These cell-cycle checkpoints are essential to prevent both replication of a damaged DNA template (GC arrest) and segregation of damaged chromosomes (G2 arrest).…”

Section: Gene Amplificationmentioning

confidence: 99%

“…These cell-cycle checkpoints are essential to prevent both replication of a damaged DNA template (GC arrest) and segregation of damaged chromosomes (G2 arrest). Presumably, the transient delays at these checkpoints permit damaged DNA to be repaired prior to these critical cellular decisions, thus enhancing cell survival and limiting the propagation of heritable genetic errors (Papathanasiou and Fornace, 1991) In the complex molecular pathways that control DNA damage-induced cell-cycle arrest, wild-type p53 protein is clearly a central component. This conclusion is based on the following findings:…”

Section: Gene Amplificationmentioning

confidence: 99%

p53--An Acrobat in Tumorigenesis

Moll

Schramm

1998

Critical Reviews in Oral Biology & Medicine

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The p53 tumor suppressor protein plays a central role in maintaining genomic integrity. It does so by occupying a nodal point in the DNA damage control pathway. When cells are subject to ionizing radiation or other mutagenic events, p53 mediates cell cycle arrest or programmed cell death (apoptosis). Furthermore, some evidence suggests that p53 plays a role in the recognition and repair of damaged DNA. Biochemically, p53 is a sequence-specific transcriptional stimulator and a nonspecific transcriptional repressor but also engages in multiple protein-protein interactions. Conversely, disruption of the p53 response pathway strongly correlates with tumorigenesis. p53 is functionally inactivated by structural mutations, neutralization by viral products, and non-mutational cellular mechanisms in the majority of human cancers. p53-deficient mice have a highly penetrant tumor phenotype, with over 90% tumor incidence within nine months. In some cancers, direct physical evidence exists identifying the p53 gene as a target of known environmental carcinogens such as UV light and benzojalpyrene in cancers of the skin and lung. When p53 loss occurs, cells do not get repaired or eliminated but rather proceed to replicate damaged DNA, which results in more random mutations, gene amplifications, chromosomal re-arrangements, and aneuploidy. In some experimental models, loss of p53 confers resistance to anticancer therapy due to loss of apoptotic competence. The translational potential of these discoveries is beginning to be tested in novel p53-based therapies.

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DNA-damage inducible genes

Cited by 14 publications

References 61 publications

Gadd45a inhibits cell migration and invasion by altering the global RNA expression

Gadd45a inhibits cell migration and invasion by altering the global RNA expression

Molecular mechanism of endothelial growth arrest by laminar shear stress

p53--An Acrobat in Tumorigenesis

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