Rapid development of glomerular injury and renal failure in mice lacking p53R2

Powell, David R.; Desai, Urvi; Sparks, Mary J.; Hansen, Gwenn M.; Schrick, Jeff; Shi, Zheng Zheng; Hicks, John; Vogel, Peter

doi:10.1007/s00467-004-1696-5

Cited by 34 publications

(35 citation statements)

References 29 publications

(38 reference statements)

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“…Methods for gene trapping in ES cells, identification of trapped genes by using OmniBank sequence tags (OSTs), and characterization of retroviral gene-trap vector insertion points are published in refs. [23][24][25][26]. OmniBank ES cell clone OST352973 was used to generate Angptl4 Ϫ/Ϫ mice as described in ref.…”

Section: Methodsmentioning

confidence: 99%

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Desai

Lee²,

Chung³

et al. 2007

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

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170

140

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We used gene knockout mice to explore the role of Angiopoietinlike-4 (Angptl4) in lipid metabolism as well as to generate antiAngptl4 mAbs with pharmacological activity. Angptl4 ؊/؊ mice had lower triglyceride (TG) levels resulting both from increased very low-density lipoprotein (VLDL) clearance and decreased VLDL production and had modestly lower cholesterol levels. Also, both Angptl4 ؊/؊ suckling mice and adult mice fed a high-fat diet showed reduced viability associated with lipogranulomatous lesions of the intestines and their draining lymphatics and mesenteric lymph nodes. Treating C57BL/6J, ApoE ؊/؊, LDLr ؊/؊, and db/db mice with the anti-Angptl4 mAb 14D12 recapitulated the lipid and histopathologic phenotypes noted in Angptl4 ؊/؊ mice. This demonstrates that the knockout phenotype reflects not only the physiologic function of the Angptl4 gene but also predicts the pharmacologic consequences of Angptl4 protein inhibition with a neutralizing antibody in relevant models of human disease. monoclonal antibody ͉ mouse ͉ triglycerides ͉ cholesterol

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Section: Methodsmentioning

confidence: 99%

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Desai

Lee²,

Chung³

et al. 2007

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

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170

140

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“…The p53 protein homolog p73 has also been shown to induce p53R2 expression after DNA damage (4). Knock-out mice lacking a functional p53R2 gene died from severe renal failure by the age of 14 weeks (17,18).It has been shown that DNA damage in budding yeast activates the Mec1/Rad53 kinases (homologs to ATR and Chk1 in mammalian cells (19)), which lead to transcriptional up-regulation of the RNR genes and degradation of the small RNR inhibitor protein Sml1 (20 -23). As a consequence, RNR activity increases, and the dNTP pools are elevated 7-fold in logarithmically growing cells, which is about 4-fold higher than the maximal level of dNTP pools during the S phase (24).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of Mammalian Ribonucleotide Reduction and dNTP Pools after DNA Damage and in Resting Cells

Håkansson

Hofer

Thelander

2006

Journal of Biological Chemistry

246

224

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Ribonucleotide reductase (RNR) provides the cell with a balanced supply of deoxyribonucleoside triphosphates (dNTP) for DNA synthesis. In budding yeast DNA damage leads to an up-regulation of RNR activity and an increase in dNTP pools, which are essential for survival. Mammalian cells contain three non-identical subunits of RNR; that is, one homodimeric large subunit, R1, carrying the catalytic site and two variants of the homodimeric small subunit, R2 and the p53-inducible p53R2, each containing a tyrosyl free radical essential for catalysis. S-phase-specific DNA replication is supported by an RNR consisting of the R1 and R2 subunits. In contrast, DNA damage induces expression of the R1 and the p53R2 subunits. We now show that neither logarithmically growing nor G o /G 1 -synchronized mammalian cells show any major increase in their dNTP pools after DNA damage. However, non-dividing fibroblasts expressing the p53R2 protein, but not the R2 protein, have reduced dNTP levels if exposed to the RNR-specific inhibitor hydroxyurea, strongly indicating that there is ribonucleotide reduction in resting cells. The slow, 4-fold increase in p53R2 protein expression after DNA damage results in a less than 2-fold increase in the dNTP pools in G o /G 1 cells, where the pools are about 5% that of the size of the pools in S-phase cells. Our results emphasize the importance of the low constitutive levels of p53R2 in mammalian cells, which together with low levels of R1 protein may be essential for the supply of dNTPs for basal levels of DNA repair and mitochondrial DNA synthesis in G o /G 1 cells. Mammalian cells need a balanced supply of deoxyribonucleoside triphosphates (dNTPs)2 for DNA replication and repair. The rate-limiting step in the formation of DNA precursors is the de novo reduction of ribonucleoside diphosphates to the corresponding deoxyribonucleoside diphosphates by the enzyme ribonucleotide reductase (RNR) (1). In S phase, the mammalian RNR enzyme is composed of the homodimeric R1 and R2 subunits, which together form a heterotetrameric active enzyme. The large R1 protein (90 kDa) carries the active site, whereas the small R2 protein (45 kDa) contains a diferric iron center generating a tyrosyl free radical necessary for catalysis (1, 2). An additional mammalian RNR protein, p53R2, was identified in 2000 (3, 4). Like the homologous R2 protein, p53R2 contains a tyrosyl free radical and forms an active RNR complex with the R1 protein in vitro (5). The tyrosyl free radical of both the R2 and the p53R2 proteins is specifically destroyed by the RNR inhibitor hydroxyurea (5, 6).Because unbalanced dNTP pools can cause genetic abnormalities and cell death (1), RNR activity is tightly regulated in mammalian cells by S-phase-specific transcription of the R1 and R2 genes (7-9), binding of nucleoside triphosphate allosteric effectors to the R1 protein (10), and anaphase promoting complex-Cdh1-mediated degradation of the R2 protein in late mitosis (11,12). In cycling cells, the S-phase-dependent activity of the RNR complex is l...

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“…p53R2 is a p53-inducible RR and participates in p53-induced DNA repair by supplying dNTP in response to various types of DNA damage (Nakano et al, 2000;Tanaka et al, 2000;Hakansson et al, 2006). The exact physiological function of p53R2 is not known, but it is essential for cell survival, because mice lacking functional p53R2 apparently grow normally up to 6 weeks but then die from kidney failure (Kimura et al, 2003;Powell et al, 2005). In addition to being a component of the RR holoenzymes, R1, R2 and p53R2 subunits seem to play an important role in determining the malignant potential of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Ribonucleotide reductase small subunit p53R2 suppresses MEK–ERK activity by binding to ERK kinase 2

et al. 2009

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The p53-dependent RR small subunit (p53R2) protein, a newly identified member of the ribonucleotide reductase family, plays a key role in the p53-dependent cellular response to DNA. Several recent studies have suggested that p53R2 also plays an important role in suppressing the invasive potential of human cancer cells. However, the cellular mechanism that regulates invasiveness remains largely unknown. In this study, we show that p53R2 interacts with MEK2 (extracellular signal-regulated kinase (ERK) kinase 2-mitogen-activated protein kinase (MAPK) kinase 2), the molecule immediately upstream of ERK in the Ras-Raf-MAPK signaling cascade. In co-immunoprecipitation and immunofluorescence analyses, we found that p53R2 and MEK2 interact physically in cultured mammalian cells, and that the p53R2 segment comprising amino acids 161-206 is critical for this interaction. Moreover, serum-induced phosphorylation of MEK1/2 and ERK1/2 was greatly augmented in human cancer cells expressing small-interfering RNA against p53R2. On the other hand, phosphorylation of MEK1/2 and ERK1/2 in human cancer cells was markedly attenuated by overexpression of p53R2. Furthermore, MEK2 was required for p53R2 knockdown-induced enhancement of the invasive ability and anchorageindependent growth of human lung cancer H1299 cells. Taken together, these findings show that p53R2 negatively modulates serum-induced MEK-ERK activity and inhibits the MEK-ERK-mediated malignancy potential of human cancer cells.

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Rapid development of glomerular injury and renal failure in mice lacking p53R2

Cited by 34 publications

References 29 publications

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Regulation of Mammalian Ribonucleotide Reduction and dNTP Pools after DNA Damage and in Resting Cells

Ribonucleotide reductase small subunit p53R2 suppresses MEK–ERK activity by binding to ERK kinase 2

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