Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer

Y. H. Kim, K. A. Kwei, L. Girard, K. Salari, J. Kao, M. Pacyna-Gengelbach, P. Wang, T. Hernandez-Boussard, A. F. Gazdar, I. Petersen, J. D. Minna, J. R. Pollack

Research output: Contribution to journalArticle

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Abstract

DNA amplifications, leading to the overexpression of oncogenes, are a cardinal feature of lung cancer and directly contribute to its pathogenesis. To uncover such novel alterations, we performed an array-based comparative genomic hybridization survey of 128 non-small-cell lung cancer cell lines and tumors. Prominent among our findings, we identified recurrent high-level amplification at cytoband 22q11.21 in 3% of lung cancer specimens, with another 11% of specimens exhibiting low-level gain spanning that locus. The 22q11.21 amplicon core contained eight named genes, only four of which were overexpressed (by transcript profiling) when amplified. Among these, CRKL encodes an adapter protein functioning in signal transduction, best known as a substrate of the BCR-ABL kinase in chronic myelogenous leukemia. RNA-interference-mediated knockdown of CRKL in lung cancer cell lines with (but not without) amplification led to significantly decreased cell proliferation, cell-cycle progression, cell survival, and cell motility and invasion. In addition, overexpression of CRKL in immortalized human bronchial epithelial cells led to enhanced growth factor-independent cell growth. Our findings indicate that amplification and resultant overexpression of CRKL contribute to diverse oncogenic phenotypes in lung cancer, with implications for targeted therapy, and highlight a role of adapter proteins as primary genetic drivers of tumorigenesis.

Original languageEnglish (US)
Pages (from-to)1421-1430
Number of pages10
JournalOncogene
Volume29
Issue number10
DOIs
StatePublished - Mar 2010

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Oncogenes
Lung Neoplasms
Comparative Genomic Hybridization
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
RNA Interference
Tumor Cell Line
Non-Small Cell Lung Carcinoma
Cell Movement
Signal Transduction
Cell Survival
Intercellular Signaling Peptides and Proteins
Cell Cycle
Carcinogenesis
Proteins
Phosphotransferases
Epithelial Cells
Cell Proliferation
Phenotype
Cell Line
DNA

Keywords

  • Adapter protein
  • CRKL
  • DNA amplification
  • Genomic profiling
  • Lung cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Kim, Y. H., Kwei, K. A., Girard, L., Salari, K., Kao, J., Pacyna-Gengelbach, M., ... Pollack, J. R. (2010). Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer. Oncogene, 29(10), 1421-1430. https://doi.org/10.1038/onc.2009.437

Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer. / Kim, Y. H.; Kwei, K. A.; Girard, L.; Salari, K.; Kao, J.; Pacyna-Gengelbach, M.; Wang, P.; Hernandez-Boussard, T.; Gazdar, A. F.; Petersen, I.; Minna, J. D.; Pollack, J. R.

In: Oncogene, Vol. 29, No. 10, 03.2010, p. 1421-1430.

Research output: Contribution to journalArticle

Kim, YH, Kwei, KA, Girard, L, Salari, K, Kao, J, Pacyna-Gengelbach, M, Wang, P, Hernandez-Boussard, T, Gazdar, AF, Petersen, I, Minna, JD & Pollack, JR 2010, 'Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer', Oncogene, vol. 29, no. 10, pp. 1421-1430. https://doi.org/10.1038/onc.2009.437
Kim, Y. H. ; Kwei, K. A. ; Girard, L. ; Salari, K. ; Kao, J. ; Pacyna-Gengelbach, M. ; Wang, P. ; Hernandez-Boussard, T. ; Gazdar, A. F. ; Petersen, I. ; Minna, J. D. ; Pollack, J. R. / Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer. In: Oncogene. 2010 ; Vol. 29, No. 10. pp. 1421-1430.
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