Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45

Zhan, Qimin; Antinore, Michael J.; Wang, Xin Wei; Carrier, F.; Smith, M. Charles; Harris, Curtis C.; Fornace, Albert J.

doi:10.1038/sj.onc.1202667

Cited by 420 publications

(348 citation statements)

References 30 publications

(35 reference statements)

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“…25,26 GADD45-b negatively regulates cell growth by interacting with cdc2 and cyclin B, thus causing G 2 /M cell-cycle arrest. 27 Both p21 WAF1 and GADD45-b have been appointed a functional role in mouse lupus development. [28][29][30] CDKN1A and PTTG1 was selected and the difference in fold induction between two lupusprone mice was confirmed by real-time PCR (Figure 3).…”

Section: Effects On Cell Growth and Deathmentioning

confidence: 99%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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Interferon (IFN)-a is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/ W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lprand normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-a treatment. Analysis of IFN-a-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-a including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/ lpr and/or BALB/c mice. Of IFN-a-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-a treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-a response in two lupus-prone models, and help to have an insight into the role of IFN-a in lupus pathogenesis Genes and Immunity (2007) IntroductionSystemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a break of immune tolerance to self antigens, resulting in inflammation and damage to a range of organ systems. The exact pathoetiology of SLE remains elusive. Elevated serum levels of IFN-a have long been observed and correlated with disease activity. A series of studies using microarray gene expression analysis in patient peripheral blood cells demonstrated an 'IFN signature' in SLE, which correlated with renal and hematological involvement of phenotypes. [1][2][3][4][5][6] Supporting evidence has also come from studies on murine lupus. The (New Zealand Black (NZB) Â New Zealand White (NZW))F1 hybrid female mice (NZB/W) develop a disease closely resembling human SLE, characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. In the NZB parental strain, which also develops a lupus-like syndrome, homozygous IFN-a/b R-deleted NZB mice had significantly reduced antierythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease and mortality. 7 In contrast to normal BALB/c mice, continuous in vivo treatment of IFN-a in pre-autoimmune NZB/W mice from 8 weeks of age precipitates the autoimmune process and kidney damage, leading to premature death from severe immune complex glomerulonephritis. This result provides a direct evidence that IFN-a is implicated in the pathogenesis of SLE. 8 Thus, the type I IFNs have emerged as a dominant target in the path...

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Section: Effects On Cell Growth and Deathmentioning

confidence: 99%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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“…22 Through its association with Cdc2, GADD45 disrupts the interactions of Cdc2 with cyclin B1 and, thus, may induce G2/M arrest. 23 The GADD genes, therefore, may represent a unique target for drugs that induce cell cycle arrest, apoptosis and differentiation such as PPARg ligands (Figure 2). GADD45 is prominently induced in growth-arrested cells 19 and in those undergoing apoptosis.…”

Section: Pparc-mediated Modulation Of Proliferation and Apoptosis D Bmentioning

confidence: 99%

New targets for PPARγ in the vessel wall: implications for restenosis

2005

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Peroxisome proliferator-activated receptor {gamma} (PPARg), the nuclear receptor that binds the insulin-sensitizing thiazolidinediones (TZDs), is prominently upregulated in intimal vascular smooth muscle cells (VSMC) after mechanical injury to the vessel wall. Several TZD PPARg ligands have been shown to inhibit neointima formation in both normal and insulinresistant vasculature. The suppression of intimal hyperplasia by TZD PPARg ligands probably results from their activity to inhibit VSMC growth and promote apoptosis. TZDs prevent VSMC proliferation by blocking the activity of regulatory proteins, such as phosphorylation of the retinoblastoma protein (Rb). Rb functions as a G 1 gatekeeper by controlling S phase gene expression mediated by the E2F transcription factor. Consistent with their effect on Rb phosphorylation, PPARg ligands inhibit the mitogenic induction of minichromosome maintenance (MCM) proteins 6 and 7, two E2F-regulated S phase genes essential for DNA replication. PPARg ligands also induced apoptosis in VSMC, which correlated with a potent induction of GADD45, a gene implicated in controlling cell growth and survival. A constitutively active form of PPARg targeted the same cell cycle regulators as did PPARg ligands, consistent with a nuclear-receptor-dependent mechanism of action. This review will summarize mechanisms through which PPARg modulates VSMC proliferation and apoptosis suggesting that PPARg itself is a novel important regulator of cell cycle and apoptosis and may provide a new therapeutic approach to prevent restenosis. Keywords: PPARg; thiazolidinedione; vascular smooth muscle; proliferation; minichromosome maintenance protein; GADD45Peroxisome proliferator-activated receptor {gamma} (PPARg) ligands have been shown to inhibit growth of vascular and cancer cells by interfering with the expression and function of multiple cell cycle regulators. 1-6 Although many studies have focused on alterations in the regulation of cell growth as a fundamental feature during atherogenesis and neointimal hyperplasia after percutaneous coronary revascularization, it is becoming increasingly evident that perturbations in the regulation of cell death may be of equal importance. 7 In vascular smooth muscle cells (VSMC), we have previously reported that the thiazolidinedione (TZD) PPARg ligands, troglitazone (TRO) and rosiglitazone (RSG), inhibit exit from G1 into S phase of the cell cycle by attenuating retinoblastoma protein (Rb) phosphorylation. 4 As illustrated in Figure 1 decreased phosphorylation of Rb by TRO and RSG likely results from their effect to elevate levels of the cyclindependent kinase inhibitor (CDKI) p27 kip1 and reduce the activity of cyclin D-and cyclin E-dependent kinases (CDK). 4 In addition, recent studies have shown that TZDs not only inhibit cell growth, but they can also induce apoptosis in VSMC. 8,9 The molecular mechanisms by which TZDs induce apoptosis in VSMC and whether they involve a PPARgdependent pathway also remain unclear.Using DNA microarray analysis, we have identifi...

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“…A slight transitional arrest was observed in G 2 /M, which may have originated from p53's ability to inhibit the p34 cdc2 /cyclin B1 complex. 25,26 This growth arrest was reversible upon temperature rise, indicating that the arrest was mediated by p53's temperature-dependent transcriptional activity.…”

Section: Discussionmentioning

confidence: 95%

Restoration of endogenous wild-type p53 activity in a glioblastoma cell line with intrinsic temperature-sensitive p53 induces growth arrest but not apoptosis

Ikeda¹,

Tada²,

Ishii³

et al. 2001

Int. J. Cancer

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p53 protein is a transcription factor involved in multiple tumor-suppressor activities including cell cycle control and apoptosis. TP53 gene is frequently mutated in glioblastoma, suggesting the importance of inactivation of this gene product in gliomagenesis. Restoration of p53 function in glioblastoma cell lines deficient for p53 has shown that p53 induces growth arrest or apoptosis depending on the cell line and vector used to transduce wild-type TP53 alleles. Considering that astrocytes grow and express p53, it is not clear whether these results reflect physiologic responses or the result of p53 overexpression in combination with cellular responses to viral vector infection. Here, we reassessed this issue using a glioblastoma cell line (LN382) that expresses an endogenous temperature-sensitive mutant p53. This cell line expresses TP53 alleles (100% as determined by a p53 transcriptional assay in yeast) mutated at codon 197 GTG (Val) > CTG (Leu). We found that the p53 protein in these cells acted as an inactive mutant at 37°C and as a functional wild-type p53 below 34°C as demonstrated by several lines of evidence, including (i) restoration of transactivating ability in yeast, (ii) induction of p53-modulated genes such as CDKN1 p21 and transforming growth factor-␣, (iii) disappearance of accumulated p53 protein in the nucleus and (iv) decrease in steady state p53 protein levels. This temperature switch allowed p53 levels, which were close to physiological levels to dramatically reduce LN382 cell proliferation by inducing a G 1 /S cell cycle block, but not to induce apoptosis. The lack of apoptosis was considered to be a result of the low level p53 expression, because increasing wild-type p53 levels by adenoviral-mediated gene transfer caused apoptosis in these cells. The LN382 cell line will be extremely useful for investigations into the roles of p53 in cellular responses to a variety of stimuli or damages.

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Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45

Cited by 420 publications

References 30 publications

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

New targets for PPARγ in the vessel wall: implications for restenosis

Restoration of endogenous wild-type p53 activity in a glioblastoma cell line with intrinsic temperature-sensitive p53 induces growth arrest but not apoptosis

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