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Point mutations in c-Myc uncouple neoplastic transformation from multiple other phenotypes in rat fibroblasts.

Graves JA, Rothermund K, Wang T, Qian W, Van Houten B, Prochownik EV - PLoS ONE (2010)

Bottom Line: In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism.Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation.These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America. gravja@chp.edu

ABSTRACT
Deregulation of c-Myc (Myc) occurs in many cancers. In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism. Although Myc is wild type in most cancers (wtMyc), it occasionally acquires point mutations in certain lymphomas. Some of these mutations confer a survival advantage despite partially attenuating proliferation and transformation. Here, we have evaluated four naturally-occurring or synthetic point mutations of Myc for their ability to affect these phenotypes, as well as to promote genomic instability, to generate reactive oxygen species and to up-regulate aerobic glycolysis and oxidative phosphorylation. Our findings indicate that many of these phenotypes are genetically and functionally independent of one another and are not necessary for transformation. Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation. One mutation (Q131R) was greatly impaired for nearly all of the studied Myc phenotypes, yet was able to retain some ability to transform. These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state.

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18F-2DG imaging by PET.Duplicate tumor-bearing mice inoculated with wtMyc, Q131R, or F138C cells were imaged by PET following injection of 18F-labeled 2DG. Dotted lines indicate tumor boundaries. Arrows indicate the urinary bladder, where the isotope is expectedly the most concentrated. The average relative SUV is indicated with the value for wtMyc set at 1.
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pone-0013717-g007: 18F-2DG imaging by PET.Duplicate tumor-bearing mice inoculated with wtMyc, Q131R, or F138C cells were imaged by PET following injection of 18F-labeled 2DG. Dotted lines indicate tumor boundaries. Arrows indicate the urinary bladder, where the isotope is expectedly the most concentrated. The average relative SUV is indicated with the value for wtMyc set at 1.

Mentions: To determine whether the metabolic defects described above may have been confined only to the in vitro setting, we used positron emissions tomography to compare the uptake of 18F-2-DG in tumor xenografts arising from wtMyc, Q131R and F138C cells. As shown in Figure 7 the latter tumors were only slightly less metabolically active than the former. From these studies, we conclude that the decrease in metabolic up-regulation seen in Q131R and F138C cells is a consistent finding that is independent of the tumor cell environment.


Point mutations in c-Myc uncouple neoplastic transformation from multiple other phenotypes in rat fibroblasts.

Graves JA, Rothermund K, Wang T, Qian W, Van Houten B, Prochownik EV - PLoS ONE (2010)

18F-2DG imaging by PET.Duplicate tumor-bearing mice inoculated with wtMyc, Q131R, or F138C cells were imaged by PET following injection of 18F-labeled 2DG. Dotted lines indicate tumor boundaries. Arrows indicate the urinary bladder, where the isotope is expectedly the most concentrated. The average relative SUV is indicated with the value for wtMyc set at 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2965668&req=5

pone-0013717-g007: 18F-2DG imaging by PET.Duplicate tumor-bearing mice inoculated with wtMyc, Q131R, or F138C cells were imaged by PET following injection of 18F-labeled 2DG. Dotted lines indicate tumor boundaries. Arrows indicate the urinary bladder, where the isotope is expectedly the most concentrated. The average relative SUV is indicated with the value for wtMyc set at 1.
Mentions: To determine whether the metabolic defects described above may have been confined only to the in vitro setting, we used positron emissions tomography to compare the uptake of 18F-2-DG in tumor xenografts arising from wtMyc, Q131R and F138C cells. As shown in Figure 7 the latter tumors were only slightly less metabolically active than the former. From these studies, we conclude that the decrease in metabolic up-regulation seen in Q131R and F138C cells is a consistent finding that is independent of the tumor cell environment.

Bottom Line: In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism.Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation.These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America. gravja@chp.edu

ABSTRACT
Deregulation of c-Myc (Myc) occurs in many cancers. In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism. Although Myc is wild type in most cancers (wtMyc), it occasionally acquires point mutations in certain lymphomas. Some of these mutations confer a survival advantage despite partially attenuating proliferation and transformation. Here, we have evaluated four naturally-occurring or synthetic point mutations of Myc for their ability to affect these phenotypes, as well as to promote genomic instability, to generate reactive oxygen species and to up-regulate aerobic glycolysis and oxidative phosphorylation. Our findings indicate that many of these phenotypes are genetically and functionally independent of one another and are not necessary for transformation. Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation. One mutation (Q131R) was greatly impaired for nearly all of the studied Myc phenotypes, yet was able to retain some ability to transform. These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state.

Show MeSH
Related in: MedlinePlus