The mutant forms of KRas, NRas and HRas drive the initiation and progression of a number of human cancers, but less is known about the role of WT (wild-type) Ras alleles and isoforms in cancer. We used zinc-finger nucleases targeting HRas and NRas to modify both alleles of these genes in the mutant KRas-driven Hec1A endometrial cancer cell line, which normally expresses WT copies of these genes. The disruption of either WT isoform of Ras compromised growth-factor-dependent signalling through the ERK (extracellular-signal-regulated kinase) pathway. In addition, the disruption of HRas hindered the activation of Akt and subsequent downstream signalling. This was associated with decreased proliferation, increased apoptosis and decreased anchorage-independent growth in the HRas-disrupted cells. However, xenograft tumour growth was not significantly affected by the disruption of either NRas or HRas. As expected, deleting the mutant allele of KRas abolished tumour growth, whereas deletion of the remaining WT copy of KRas increased the tumorigenic properties of these cells; deleting a single copy of either HRas or NRas did not mimic this effect. The present study demonstrates that the WT copies of HRas, NRas and KRas play unique roles in the context of mutant KRas-driven tumours.
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June 2013
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Research Article|
May 10 2013
A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation
Carolyn Bentley
;
Carolyn Bentley
*Department of Discovery Oncology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Stefanie S. Jurinka
;
Stefanie S. Jurinka
*Department of Discovery Oncology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Noelyn M. Kljavin
;
Noelyn M. Kljavin
†Department of Molecular Biology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Steffan Vartanian
;
Steffan Vartanian
*Department of Discovery Oncology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Sree R. Ramani
;
Sree R. Ramani
‡Department of Protein Chemistry, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Lino C. Gonzalez
;
Lino C. Gonzalez
‡Department of Protein Chemistry, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Kebing Yu
;
Kebing Yu
‡Department of Protein Chemistry, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Zora Modrusan
;
Zora Modrusan
†Department of Molecular Biology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Pan Du
;
Pan Du
§Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Richard Bourgon
;
Richard Bourgon
§Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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Richard M. Neve
;
Richard M. Neve
*Department of Discovery Oncology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
†Department of Molecular Biology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
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David Stokoe
David Stokoe
1
*Department of Discovery Oncology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
†Department of Molecular Biology, Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, U.S.A.
1To whom correspondence should be addressed (email stokoe.david@gene.com).
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Biochem J (2013) 452 (2): 313–320.
Article history
Received:
October 15 2012
Revision Received:
February 20 2013
Accepted:
March 18 2013
Accepted Manuscript online:
March 18 2013
Citation
Carolyn Bentley, Stefanie S. Jurinka, Noelyn M. Kljavin, Steffan Vartanian, Sree R. Ramani, Lino C. Gonzalez, Kebing Yu, Zora Modrusan, Pan Du, Richard Bourgon, Richard M. Neve, David Stokoe; A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation. Biochem J 1 June 2013; 452 (2): 313–320. doi: https://doi.org/10.1042/BJ20121578
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