p53-Mediated DNA Repair Responses to UV Radiation: Studies of Mouse Cells Lacking p53, p21, and/orgadd45 Genes

Smith, Martin L.; Ford, James M.; Hollander, M. Christine; Bortnick, Rachel; Amundson, Sally A.; Seo, Young Rok; Deng, Chu‐Xia; Hanawalt, Philip C.; Fornace, Albert J.

doi:10.1128/mcb.20.10.3705-3714.2000

Cited by 391 publications

(265 citation statements)

References 38 publications

(87 reference statements)

Supporting

Mentioning

247

Contrasting

Unclassified

Order By: Relevance

“…GADD45B and GADD45G are members of the GADD45 family of proteins that are induced by genotoxic stresses and various apoptotic cytokines [11][12][13] and are involved in cell cycle arrest, [14][15][16][17][18][19] DNA repair, [20][21][22] cell survival, [22][23][24][25][26][27] and apoptosis. These functions are mediated by proliferating cell nuclear antigen (PCNA), cell division control 2 (CDC2), cyclin B1 (CCNB1), and cyclin-dependent kinase inhibitor 1A (CDKN1A; also known as p21), which are classified in the GO "cell cycle" category.…”

Section: Molecularmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Responses of Human Lung Epithelial Cells to the Toxicity of Copper Oxide Nanoparticles Inferred from Whole Genome Expression Analysis

et al. 2011

View full text Add to dashboard Cite

This study proposes a molecular mechanism for lung epithelial A549 cells response to copper oxide nanoparticles (CuO-NPs) related to Cu ions released from CuO-NPs. Cells that survived exposure to CuO-NPs arrested the cell cycle as a result of the downregulation of proliferating cell nuclear antigen (PCNA), cell division control 2 (CDC2), cyclin B1 (CCNB1), target protein for Xklp2 (TPX2), aurora kinase A (AURKA) and B (AURKB). Furthermore, cell death was avoided through the induced expression of nuclear receptors NR4A1 and NR4A3, and growth arrest and DNA damage-inducible 45 β and γ (GADD45B and GADD45G, respectively). The downregulation of CDC2, CCNB1, TPX2, AURKA, and AURKB, the expressions of which are involved in cell cycle arrest, was attributed to Cu ions released from CuO-NPs into medium. NR4A1 and NR4A3 expression was also induced by Cu ions released into medium. The expression of GADD45B and GADD45G activated the p38 pathway that was involved in escape from cell death. The upregulation of GADD45B and GADD45G was not observed with Cu ions released into medium but was observed in cells exposed to CuO-NPs. However, because the expression of the genes was also

show abstract

Section: Molecularmentioning

confidence: 99%

“…PCNA is involved in DNA repair and the transition from the G1 to the S phase of the cell cycle. [20][21][22] In contrast, CDKN1A inhibits PCNA and blocks the transition from the G1 to the S phase of the cell cycle. 20,38 The CDC2-CCNB1 complex is required for the transition from the G2 to the M phase.…”

Section: Molecularmentioning

confidence: 99%

Molecular Responses of Human Lung Epithelial Cells to the Toxicity of Copper Oxide Nanoparticles Inferred from Whole Genome Expression Analysis

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Using gadd45 KO MEFs (24) and RKO cells expressing antisense gadd45 RNA in clonogenic survival assays, has shown that deficiency of gadd45 increases the sensitivity of cells to killing by UV irradiation or cisplatin (25). Recently, Gadd45b has been suggested to play a role in TNFa-NF-kB mediated cell survival (26), and to mediate the protective effects of CD40 co-stimulation against Fas-induced apoptosis (37).…”

Section: Gadd45 Proteins Have Been Implicated In Cycle Arrestmentioning

confidence: 99%

“…Recently, Gadd45b has been suggested to play a role in TNFa-NF-kB mediated cell survival (26), and to mediate the protective effects of CD40 co-stimulation against Fas-induced apoptosis (37). The role Gadd45 proteins play in DNA repair (11,(23)(24) is compatible with a survival function.…”

Section: Gadd45 Proteins Have Been Implicated In Cycle Arrestmentioning

confidence: 99%

Gadd45 in the response of hematopoietic cells to genotoxic stress

Liebermann

Hoffman

2007

Blood Cells, Molecules, and Diseases

View full text Add to dashboard Cite

Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in either cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Recently we have taken advantage of gadd45a and gadd45b deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. Myeloid enriched BM cells from gadd45a and gadd45b deficient mice were observed to be more sensitive to ultraviolet radiation (UVC), VP-16 and daunorubicin (DNR) induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a and gadd45b deficient cells was evident also by enhanced activation of caspase-3 and PARP cleavage and decreased expression of cIAP-1, Bcl-2, Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45 deficient BM cells restored the wt apoptotic phenotype. Both gadd45a and gadd45b deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Additional work conducted in this laboratory has shown that in hematopoietic cells exposed to UV radiation gaddd45a and gadd45b cooperate to promote cell survival via two distinct signaling pathways involving activation of the Gadd45a-p38-NF-kB mediated survival pathway and Gadd45b mediated inhibition of the stress response MKK4-JNK pathway (59). These data reveal novel mechanisms that mediate the pro-survival functions of gadd45a and gadd45b in hematopoietic cells following UV irradiation. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs. This knowledge should contribute to a greater understanding of the genetic events involved in the pathogenesis of different leukaemias and response of normal and malignant hematopoietic cells to chemo and radiation therapy. These observations set the stage to evaluate, in clinically relevant settings, the impact that the status of gadd45a and gadd45b might have on the efficacy of DNR or VP-16 in killing leukemic cells.

show abstract

“…Inherited mutations in DNA repair enzymes can increase the incidence of these tumors, and p53 alterations have also been reported. 13,14 We previously documented DNA copy number alterations in a cohort of 10 snap-frozen conjunctival squamous cell carcinoma tumor specimens and two in situ carcinomas by array-based comparative genomic hybridization assay, which allowed us to determine the most frequent DNA gains and losses. 15 We now compare transcriptional profiles of nine of these tumor specimens from a single center in Saudi Arabia to normal conjunctiva in order to identify dysregulated mRNAs representing molecular targets potentially useful for diagnosis and/or therapy.…”

mentioning

confidence: 99%

Altered gene expression in conjunctival squamous cell carcinoma

et al. 2016

View full text Add to dashboard Cite

Conjunctival squamous cell carcinoma is a malignancy of the ocular surface. The molecular drivers responsible for the development and progression of this disease are not well understood. We therefore compared the transcriptional profiles of eight snap-frozen conjunctival squamous cell carcinomas and one in situ lesion with normal conjunctival specimens in order to identify diagnostic markers or therapeutic targets. RNA was analyzed using oligonucleotide microarrays, and a wide range of transcripts with altered expression identified, including many dysregulated in carcinomas arising at other sites. Among the upregulated genes, we observed more than 30-fold induction of the matrix metalloproteinases, MMP-9 and MMP-11, as well as a prominent increase in the mRNA level of a calcium-binding protein important for the intracellular calcium signaling, S100A2, which was induced over 20-fold in the tumor cohort. Clusterin was the most downregulated gene, with an approximately 180-fold reduction in the mRNA expression. These alterations were all confirmed by qPCR in the samples used for initial microarray analysis. In addition, immunohistochemical analysis confirmed the overexpression of MMP-11 and S100A2, as well as reductions in clusterin, in several independent in situ carcinomas of conjunctiva. These data identify a number of alterations, including upregulation of MMP-9, MMP-11, and S100A2, as well as downregulation of clusterin, associated with epithelial tumorigenesis in the ocular surface.

show abstract

p53-Mediated DNA Repair Responses to UV Radiation: Studies of Mouse Cells Lacking p53, p21, and/orgadd45 Genes

Cited by 391 publications

References 38 publications

Molecular Responses of Human Lung Epithelial Cells to the Toxicity of Copper Oxide Nanoparticles Inferred from Whole Genome Expression Analysis

Molecular Responses of Human Lung Epithelial Cells to the Toxicity of Copper Oxide Nanoparticles Inferred from Whole Genome Expression Analysis

Gadd45 in the response of hematopoietic cells to genotoxic stress

Altered gene expression in conjunctival squamous cell carcinoma

Contact Info

Product

Resources

About