CAD, a c-Myc target gene, is not deregulated in Burkitt's lymphoma cell lines

Mac, Susanna; Farnham, Peggy J.

doi:10.1002/(sici)1098-2744(200002)27:2<84::aid-mc4>3.0.co;2-3

Cited by 9 publications

(4 citation statements)

References 33 publications

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“…4B and C). The levels of cad mRNA decreased to basal levels by 14 to 16 h, consistent with results obtained with other cell lines, including NIH 3T3 and Rat1 fibroblasts (8,34). In the presence of inactive Brg1, cad was derepressed threefold under conditions that should have induced silencing (Fig.…”

Section: Resultssupporting

confidence: 89%

mSin3A/Histone Deacetylase 2- and PRMT5-Containing Brg1 Complex Is Involved in Transcriptional Repression of the Myc Target Gene cad

Pal

Yun

Datta

et al. 2003

Molecular and Cellular Biology

218

237

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The role of hSWI/SNF complexes in transcriptional activation is well characterized; however, little is known about their function in transcriptional repression. We have previously shown that subunits of the mSin3A/ histone deacetylase 2 (HDAC2) corepressor complex copurify with hSWI/SNF complexes. Here we show that the type II arginine-specific methyltransferase PRMT5, which is involved in cyclin E repression, can be found in association with Brg1 and hBrm-based hSWI/SNF complexes. We also show that hSWI/SNF-associated PRMT5 can methylate hypoacetylated histones H3 and H4 more efficiently than hyperacetylated histones H3 and H4. Protein-protein interaction studies indicate that PRMT5 and mSin3A interact with the same hSWI/ SNF subunits as those targeted by c-Myc. These observations prompted us to examine the expression profile of the c-Myc target genes, carbamoyl-phosphate synthase-aspartate carbamoyltransferase-dihydroorotase (cad) and nucleolin (nuc). We found that cad repression is altered in cells that express inactive Brg1 and in cells treated with the HDAC inhibitor depsipeptide. Using chromatin immunoprecipitation assays, we found that Brg1, mSin3A, HDAC2, and PRMT5 are directly recruited to the cad promoter. These results suggest that hSWI/SNF complexes, through their ability to interact with activator and repressor proteins, control expression of genes involved in cell growth and proliferation.During cell growth and differentiation several genes become either repressed or activated. These variations in expression often correlate with changes in chromatin structure and occur in the context of the cell cycle. Recruitment of the highly related Brg1 and hBrm chromatin remodeling complexes, which can disrupt nucleosome structure and increase accessibility to DNA, has been implicated in transcriptional activation of many inducible genes (21, 41). However, in view of recent findings, which show that subunits of mSin3/histone deacetylase (HDAC) corepressor complexes can be found in association with Brg1 and hBrm chromatin remodelers and that HDACs 1 and 2 are integral components of the NuRD complex, it appears that ATP-dependent chromatin remodeling might also be involved in transcriptional repression (32,51,56,63,65). Consistent with this notion, mutation of yeast SWI2/ SNF2 can lead to gene derepression (28,35,53). Furthermore, Brg1, hBrm, and

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Section: Resultssupporting

confidence: 89%

mSin3A/Histone Deacetylase 2- and PRMT5-Containing Brg1 Complex Is Involved in Transcriptional Repression of the Myc Target Gene cad

Pal

Yun

Datta

et al. 2003

Molecular and Cellular Biology

218

237

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“…The lack of apparent correlation between myc-induced genes, genes down-regulated in c-myc null cells, and genes required for transformation by c-myc remains puzzling (31). For example, carbonyl-phosphate synthetase-aspartate transcarbamylasedihydro-orotase gene expression clearly responds to loss of c-myc, but carbonyl-phosphate synthetase-aspartate transcarbamylase-dihydro-orotase apparently plays little role in tumors induced by c-myc (32). Recently, down-regulation of the expression of the H-ferritin gene was shown to be required for cell transformation by c-myc (33).…”

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confidence: 99%

Activated eIF4E-binding Protein Slows G1 Progression and Blocks Transformation by c-myc without Inhibiting Cell Growth

Lynch

FitzGerald

Johnston

et al. 2004

Journal of Biological Chemistry

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Translation initiation is poised between global regulation of cell growth and specific regulation of cell division. The mRNA cap-binding protein (eIF4E) is a critical integrator of cell growth and division because it is ratelimiting for translation initiation and is also rate-limiting for G 1 progression. Translation initiation factor eIF4E is also oncogenic and a candidate target of c-myc. Recently, an activated inhibitory 4E-binding protein (4EBP) that blocks eIF4E was used to study its regulation of Drosophila growth. We adopted this approach in mammalian cells after identifying an autosensing mechanism that protects against increased levels of 4EBP1. Increased 4EBP1 induced a quantitative increase in the inactivated phosphorylated form of 4EBP1 in vitro and in vivo. To overcome this protective mechanism, we introduced alanine substitutions at four phosphorylation/ inactivation sites in 4EBP1 to constitutively activate a 4EBP to block eIF4E. Overexpression of activated 4EBP inhibited cell proliferation and completely blocked transformation by both eIF4E and c-myc, although it did not block all tested oncogenes. Surprisingly, expression of the activated 4EBP increased cell size and protein content. Activated 4EBP blocked both cell proliferation and c-myc transformation by inhibiting G 1 progression and increasing apoptosis, without decreasing protein synthesis. Our results identify mammalian eIF4E as rate-limiting for cell cycle progression before it regulates cell growth. It further identifies G 1 control by translation initiation factors as an essential genetic target of c-myc that is necessary for its ability to transform cells.

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“…Most cancer occurs with hyperactivation of CAD, as well as the upstream, mTORC1 [51]. Besides, C-Myc, a hallmark of human cancers, also up-regulates CAD expression by binding with CAD E-box sequence in cancer cells [35,89]. Rapamycin-based mTOR inhibitors have been introduced into several clinical trials in the past couple of years.…”

Section: Cad and Tumorsmentioning

confidence: 99%

Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential

Wang

et al. 2021

IJMS

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CAD (Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase) is a multifunctional protein that participates in the initial three speed-limiting steps of pyrimidine nucleotide synthesis. Over the past two decades, extensive investigations have been conducted to unmask CAD as a central player for the synthesis of nucleic acids, active intermediates, and cell membranes. Meanwhile, the important role of CAD in various physiopathological processes has also been emphasized. Deregulation of CAD-related pathways or CAD mutations cause cancer, neurological disorders, and inherited metabolic diseases. Here, we review the structure, function, and regulation of CAD in mammalian physiology as well as human diseases, and provide insights into the potential to target CAD in future clinical applications.

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CAD, a c-Myc target gene, is not deregulated in Burkitt's lymphoma cell lines

Cited by 9 publications

References 33 publications

mSin3A/Histone Deacetylase 2- and PRMT5-Containing Brg1 Complex Is Involved in Transcriptional Repression of the Myc Target Gene cad

mSin3A/Histone Deacetylase 2- and PRMT5-Containing Brg1 Complex Is Involved in Transcriptional Repression of the Myc Target Gene cad

Activated eIF4E-binding Protein Slows G1 Progression and Blocks Transformation by c-myc without Inhibiting Cell Growth

Pyrimidine Biosynthetic Enzyme CAD: Its Function, Regulation, and Diagnostic Potential

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