The GADD45 Inhibition of Cdc2 Kinase Correlates with GADD45-mediated Growth Suppression

Jin, Shunqian; Antinore, Michael J.; Lung, Feng‐Di T.; Dong, Xin; Zhao, Hongcheng; Fan, Feiyue; Colchagie, Amy B.; Blanck, Patricia; Roller, Peter P.; Fornace, Albert J.; Zhan, Qimin

doi:10.1074/jbc.m000284200

Cited by 184 publications

(148 citation statements)

References 41 publications

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“…GADD45 has been shown to bind proliferating cell nuclear antigen and induce G 2 -M arrest in part by inhibiting Cdc2 protein kinase activity (Jin et al, 2000;Zhan et al, 1999). As shown in Figure 6c, GADD45 was highly induced by DNp63a but not by p63a.…”

Section: Discussionmentioning

confidence: 69%

p63α and ΔNp63α can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes

2001

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The p53 tumor suppressor protein plays a critical role in the regulation of the cell cycle and apoptosis. The importance of p53's functions is underscored by the high incidence of p53 mutations in human cancers. Recently, two p53-related proteins, p73 and p63, were identi®ed as members of the p53 gene family. Multiple isoforms of p73 have been found, including DN variants in which the N-termini are truncated. p63 is expressed as three major forms, p63a, p63b and p63g, each of which di er in their C-termini. All three forms can be alternatively transcribed from a cryptic promoter located within intron 3, producing DNp63a, DNp63b and DNp63g. The high degree of similarity of p73 and p63 to evolutionarily conserved regions of p53 suggests that these proteins play an important and potentially redundant role in regulating cell cycle arrest and apoptosis. Here we describe the characterization of cell lines generated to inducibly express p63a and DNp63a. We have found that p63a and DNp63a can di erentially regulate endogenous p53 target genes and induce cell cycle arrest and apoptosis. Deletion of the N-terminal 26 amino acids of DNp63a abolished its ability to transactivate p53 target genes and induce cell cycle arrest and apoptosis. This indicates that a putative transactivation domain exists within the N-terminus of the DN variants of p63. Furthermore, the di erential regulation of p53 target genes by p63a and DNp63a suggests that p63 and p53 utilize both similar and di erent signaling pathways to execute their cellular functions. Oncogene (2001) 20, 3193 ± 3205.

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Section: Discussionmentioning

confidence: 69%

p63α and ΔNp63α can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes

2001

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“…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%

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

et al. 2011

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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

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“…Cdc2/cyclinB1-Gadd45a also interacts with cdc2 (Cdk1), inhibiting of the kinase activity of the cdc2/cyclinB1 complex (2,(40)(41)(42) that is known to play a key role in transition of cells from the G2 to the M phase of the cell cycle (43)(44). This interaction has been implicated in Gadd45a mediated activation of the G2/M checkpoint in response to certain genotoxic stress agents (21).…”

Section: Unpublished and 11)mentioning

confidence: 99%

Gadd45 in the response of hematopoietic cells to genotoxic stress

Liebermann

Hoffman

2007

Blood Cells, Molecules, and Diseases

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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.

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The GADD45 Inhibition of Cdc2 Kinase Correlates with GADD45-mediated Growth Suppression

Cited by 184 publications

References 41 publications

p63α and ΔNp63α can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes

p63α and ΔNp63α can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes

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

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