This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by James, R. M. Articles by Patek, C. E. Search for Related Content PubMed PubMed Citation Articles by James, R. M. Articles by Patek, C. E.

---

Cancer Genes and Genomics

K-ras Proto-Oncogene Exhibits Tumor Suppressor Activity As Its Absence Promotes Tumorigenesis in Murine Teratomas¹

¹ Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom;
² University of Cambridge Pathology Department, Addenbrooke's Hospital, Cambridge, United Kingdom;
³ Comparative and Developmental Genetics Section, MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom; and
⁴ Division of Reproductive and Developmental Sciences, Genes and Development Group, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom

Requests for reprints: Roberta M. James, Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, United Kingdom. Phone: 44-131-651-1080; Fax: 44-131-651-1072. E-mail: roberta.james{at}ed.ac.uk

Ras proteins transduce signals from membrane-bound receptors via multiple downstream effector pathways and thereby affect fundamental cellular processes, including proliferation, apoptosis, and differentiation. K-ras activating mutations play a key role in neoplastic progression and are particularly prevalent in colorectal, pancreatic, and lung cancers. The present study addressed whether the K-ras proto-oncogene displays a tumor suppressor function by comparative analysis of mouse teratomas derived from wild-type embryonic stem (ES) cells, K-ras null (K-ras^-/-) ES cells, and K-ras^-/- ES cells that stably reexpress either wild-type K-ras^gly12 or oncogenic K-ras^val12. K-ras^-/- and K-ras^val12 teratomas were significantly larger than teratomas that expressed wild-type K-ras, contained significantly higher proportions of undifferentiated embryonal carcinoma-like cells, and showed significantly increased mitotic activity. However, K-ras^val12 but not K-ras^-/- teratomas exhibited significantly higher levels of apoptosis than wild-type teratomas. K-ras^-/- and K-ras^val12 ES cells showed a higher capacity for stem cell self-renewal in vitro compared with wild-type ES cells, and reexpression of K-ras^gly12 in K-ras^-/- ES cells restored the K-ras^-/- phenotype to wild-type values. Thus, in view of evidence that tumors can derive from tissue stem cells and that tumors harbor "cancer stem cells," aberrant K-ras expression could promote neoplastic progression by increasing their capacity for self-renewal.

Key Words: K-ras • tumor suppressor • stem cell • self-renewal • teratoma

This article has been cited by other articles:

				F. Dayyani, J. Wang, J.-R. J. Yeh, E.-Y. Ahn, E. Tobey, D.-E. Zhang, I. D. Bernstein, R. T. Peterson, and D. A. Sweetser Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival Blood, April 15, 2008; 111(8): 4338 - 4347. [Abstract] [Full Text] [PDF]

				B. Binetruy, L. Heasley, F. Bost, L. Caron, and M. Aouadi Concise Review: Regulation of Embryonic Stem Cell Lineage Commitment by Mitogen-Activated Protein Kinases Stem Cells, May 1, 2007; 25(5): 1090 - 1095. [Abstract] [Full Text] [PDF]

				Z. Hao, X. Li, T. Qiao, J. Zhang, X. Shao, and D. Fan Distribution of CIAPIN1 in Normal Fetal and Adult Human Tissues J. Histochem. Cytochem., April 1, 2006; 54(4): 417 - 426. [Abstract] [Full Text] [PDF]

				Z.-R. Yuan, R. Wang, J. Solomon, X. Luo, H. Sun, L. Zhang, and Y. Shi Identification and Characterization of Survival-Related Gene, a Novel Cell Survival Gene Controlling Apoptosis and Tumorigenesis Cancer Res., December 1, 2005; 65(23): 10716 - 10724. [Abstract] [Full Text] [PDF]

				R. Diaz, L. Lopez-Barcons, D. Ahn, A. Garcia-Espana, A. Yoon, J. Matthews, R. Mangues, R. Perez-Soler, and A. Pellicer Complex effects of Ras proto-oncogenes in tumorigenesis Carcinogenesis, April 1, 2004; 25(4): 535 - 539. [Abstract] [Full Text] [PDF]