| Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. | |
| | |
MedLine Citation:
|
PMID: 21098704 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Previous studies indicate that oncogenic stress activates the ATR-Chk1 pathway. Here, we show that ATR-Chk1 pathway engagement is essential for limiting genomic instability following oncogenic Ras transformation. ATR pathway inhibition in combination with oncogenic Ras expression synergistically increased genomic instability, as quantified by chromatid breaks, sister chromatid exchanges, and H2AX phosphorylation. This level of instability was significantly greater than that observed following ATR suppression in untransformed control cells. In addition, consistent with a deficiency in long-term genome maintenance, hypomorphic ATR pathway reduction to 16% of normal levels was synthetic lethal with oncogenic Ras expression in cultured cells. Notably, elevated genomic instability and synthetic lethality following suppression of ATR were not due to accelerated cycling rates in Ras-transformed cells, indicating that these synergistic effects were generated on a per-cell-cycle basis. In contrast to the synthetic lethal effects of hypomorphic ATR suppression, subtle reduction of ATR expression (haploinsufficiency) in combination with endogenous levels of K-ras(G12D) expression elevated the incidence of lung adenocarcinoma, spindle cell sarcoma, and thymic lymphoma in p53 heterozygous mice. K-ras(G12D)-induced tumorigenesis in ATR(+/-)p53(+/-) mice was associated with intrachromosomal deletions and loss of wild-type p53. These findings indicate that synergistic increases in genomic instability following ATR reduction in oncogenic Ras-transformed cells can produce 2 distinct biological outcomes: synthetic lethality upon significant suppression of ATR expression and tumor promotion in the context of ATR haploinsufficiency. These results highlight the importance of the ATR pathway both as a barrier to malignant progression and as a potential target for cancer treatment. |
| | |
Authors:
|
Oren Gilad; Barzin Y Nabet; Ryan L Ragland; David W Schoppy; Kevin D Smith; Amy C Durham; Eric J Brown |
Related Documents
:
|
17611224 - The drosophila hmg-domain proteins soxneuro and dichaete direct trichome formation via ... 19914214 - Endothelin-2 is upregulated in basal cell carcinoma under control of hedgehog signaling... 19882724 - Cyclic nrarp mrna expression is regulated by the somitic oscillator but nrarp protein l... 12928374 - Surface expression of notch1 on thymocytes: correlation with the double-negative to dou... 1748004 - Changes in the concentration of mrnas for the inhibin subunits in ovarian follicles aft... 9771904 - Simulated microgravity inhibits the genetic expression of interleukin-2 and its recepto... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-23 |
Journal Detail:
|
Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Dec |
Date Detail:
|
Created Date: 2010-12-08 Completed Date: 2011-02-10 Revised Date: 2011-12-21 |
Medline Journal Info:
|
Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
|
Languages: eng Pagination: 9693-702 Citation Subset: IM |
Affiliation:
|
Abramson Family Cancer Research Institute and Department of Cancer Biology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Antineoplastic Agents, Hormonal / pharmacology Blotting, Western Cell Cycle Proteins / genetics*, metabolism Cell Transformation, Neoplastic / genetics Cells, Cultured Dose-Response Relationship, Drug Female Gene Expression Regulation, Neoplastic Genes, ras / genetics* Genomic Instability* Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout NIH 3T3 Cells Neoplasms, Experimental / genetics*, metabolism, pathology Protein Kinases / genetics, metabolism Protein-Serine-Threonine Kinases / genetics*, metabolism RNA Interference Recombination, Genetic / drug effects Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Tamoxifen / pharmacology Tumor Suppressor Protein p53 / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
|
R01 AG027376-04/AG/NIA NIH HHS; R01 AG027376-04S1/AG/NIA NIH HHS; R01AG027376/AG/NIA NIH HHS; R25CA101871/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Antineoplastic Agents, Hormonal; 0/Cell Cycle Proteins; 0/Tumor Suppressor Protein p53; 10540-29-1/Tamoxifen; EC 2.7.-/Protein Kinases; EC 2.7.1.-/Atr protein, mouse; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Homotypic gap junctional communication associated with metastasis suppression increases with PKA act...
Next Document: p21CIP-1/WAF-1 induction is required to inhibit prostate cancer growth elicited by deficient express...