Human P53, Mutated at Codon 273, Causes Distinct Effects on Nucleotide Biosynthesis Salvage Pathway Key Enzymes in Rat-1 Cells and in Their Derivatives Expressing Activated ras Oncogene

Khramtsova, S. N.; Stromskaya, T. P.; Потапова, Г. И.; Chumakov, Peter M.; Копнин, Б. П.

doi:10.1006/bbrc.1993.1831

Cited by 5 publications

(3 citation statements)

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“…(21) Cell death data were acquired on a BD FACSCalibur flow cytometer (BD Biosciences, San Jose, CA) and analyzed using CellQuest software. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium inner salt (MTS) assay (25) (Promega, Madison, WI) was used to assess cell proliferation. Data are expressed as % reduction in metabolic activity i.e.…”

Section: Methodsmentioning

confidence: 99%

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Sharma

Janocha

Hill

et al. 2014

Molecular Cancer Research

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mTORC1 activation occurs frequently in cancers, yet clinical efficacy of rapalogs is limited due to the associated activation of upstream survival pathways. An alternative approach is to inhibit downstream of mTORC1; therefore, acquired resistance to fludarabine (Flu), a purine analog and anti-metabolite chemotherapy, active agent for chronic lymphocytic leukemia (CLL) was investigated. Elevated phospho-p70S6K (T389), an mTORC1 activation marker, predicted Flu resistance in a panel of B-cell lines, isogenic Flu-resistant (FluR) derivatives, and primary human CLL cells. Consistent with the anabolic role of mTORC1, FluR cells had higher rates of glycolysis and oxidative phosphorylation than Flu-sensitive (FluS) cells. Rapalogs (everolimus, rapamycin), induced moderate cell death in FluR and primary CLL cells, and everolimus significantly inhibited glycolysis and oxidative phosphorylation in FluR cells. Strikingly, the higher oxidative phosphorylation in FluR cells was not coupled to higher ATP synthesis. Instead it contributed primarily to an essential, dihydroorotate dehydrogenase (DHODH) catalyzed, step in de novo pyrimidine biosynthesis. mTORC1 promotes pyrimidine biosynthesis by p70S6 kinase-mediated phosphorylation of CAD (Ser1859) and favors S-phase cell cycle progression. We found increased phospho-CAD (S1859) and higher S-phase population in FluR cells. Pharmacological inhibition of de novo pyrimidine biosynthesis using N-phosphonacetyl-L-aspartate (PALA) and leflunomide, RNAi-mediated knockdown of p70S6K, and inhibition of mitochondrial respiration were selectively cytotoxic to FluR, but not FluS cells. These results reveal a novel link between mTORC1-mediated metabolic reprogramming and Flu resistance identifying mitochondrial respiration and de novo pyrimidine biosynthesis as potential therapeutic targets. Implications This study provides the first evidence for mTORC1/p70S6K-dependent regulation of pyrimidine biosynthesis in a relevant disease setting.

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Section: Methodsmentioning

confidence: 99%

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Sharma

Janocha

Hill

et al. 2014

Molecular Cancer Research

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“…Changes in morphology and growth parameters of Rat 1 cell sublines transformed by pPS/hygro-ras were described by us earlier [15].…”

Section: Expression Vectors Isolation Of Cell Sublines Expressing Exmentioning

confidence: 79%

Cell‐specific effects of RAS oncogene and protein kinase C agonist TPA on P‐glycoprotein function

Stromskaya¹,

Grigorian²,

Ossovskaya

et al. 1995

FEBS Letters

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We compared the influence of exogenous N-ras oncogene and treatment with PKC agonist 12-O-tetradecanoylphorbol-13-acetate (TPA) on P-glycoprotein (Pgp) function in various human, rat and dog cell lines. Two approaches were used: (a) flow cytometry analysis of Rhodamine 123 (Rh123) exclusion; and (b) sensitivity to cytotoxic action of colchicine. We have found that in Ratl fibroblasts, rat IAR2 epithelial cells and rat McA RH 7777 (hepatoma), ras activates Pgp function, while in MDCK (dog kidney), K562 (human chronic myelogenous leukaemia) and LIM1215 (human colon carcinoma) cells it either has no effect or even acts in opposite direction. TPA-induced Pgp function shows dissimilar pattern of cell specificity. It is assumed that PKC and ras oncogene regulate mdrl gene expression through at least partially distinct signalling pathways.

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“…To what extent the extracellular ectonucleotidase activity of ENTPD5 contributes to mtp53’s GOF remains to be seen. Apart from the Chumakov group’s report on the ability of mtp53 R273H to regulate the key enzymes in the nucleotide biosynthesis salvage pathway [ 85 ], the study from our group [ 73 ] is the first comprehensive work implicating mtp53 in the control of NMG, and hence adds another contribution to the already sprawling mtp53 GOF repertoire. Significantly, the expression of oncogenic myc, a known regulator of NMG expression [ 63 ] and a target of mtp53 transcriptional activity [ 86 ], was not affected by mtp53 knockdown [ 73 ], eliminating the possibility that mtp53 indirectly induces NMG expression by upregulating myc.…”

Section: Control Of Nucleotide Metabolism By Mtp53mentioning

confidence: 99%

Control of Nucleotide Metabolism Enables Mutant p53’s Oncogenic Gain-of-Function Activity

Schmidt

Nagar

Martínez

2017

IJMS

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Since its discovery as an oncoprotein in 1979, investigation into p53’s many identities has completed a full circle and today it is inarguably the most extensively studied tumor suppressor (wild-type p53 form or WTp53) and oncogene (mutant p53 form or mtp53) in cancer research. After the p53 protein was declared “Molecule of the Year” by Science in 1993, the p53 field exploded and a plethora of excellent reviews is now available on every aspect of p53 genetics and functional repertoire in a cell. Nevertheless, new functions of p53 continue to emerge. Here, we discuss a novel mechanism that contributes to mtp53’s Gain of Functions GOF (gain-of-function) activities and involves the upregulation of both nucleotide de novo synthesis and nucleoside salvage pathways.

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Human P53, Mutated at Codon 273, Causes Distinct Effects on Nucleotide Biosynthesis Salvage Pathway Key Enzymes in Rat-1 Cells and in Their Derivatives Expressing Activated ras Oncogene

Cited by 5 publications

References 0 publications

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Targeting mTORC1–Mediated Metabolic Addiction Overcomes Fludarabine Resistance in Malignant B Cells

Cell‐specific effects of RAS oncogene and protein kinase C agonist TPA on P‐glycoprotein function

Control of Nucleotide Metabolism Enables Mutant p53’s Oncogenic Gain-of-Function Activity

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