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, 7 (29), 46717-46733

Kirsten Ras* Oncogene: Significance of Its Discovery in Human Cancer Research


Kirsten Ras* Oncogene: Significance of Its Discovery in Human Cancer Research

Nobuo Tsuchida et al. Oncotarget.


The KRAS/ K-RAS oncogene is crucially involved in human cancer. The term "oncogene" -- i.e., a gene able to transform a normal cell into a tumor cell - was introduced in 1969, but the word was not used in the human carcinogenesis literature until much later. Transforming Kras and Hras oncogenes from the Kirsten and Harvey sarcoma viruses were not identified until the early 1980s due to the complicated structures of the viral genomes. Orthologs of these viral oncogenes were then found in transforming DNA fragments in human cancers in the form of mutated versions of the HRAS and KRAS proto-oncogenes. Thus, RAS genes were the first human oncogenes to be identified. Subsequent studies showed that mutated KRAS acted as an in vivo oncogenic driver, as indicated by studies of anti-EGFR therapy for metastatic colorectal cancers. This review addresses the historical background and experimental studies that led to the discovery of Kirsten Ras as an oncogene, the role of mutated KRAS in human carcinogenesis, and recent therapeutic studies of cancer cells with KRAS mutations.

Keywords: EGFR-targeted therapy; K-ras; KRAS; Kirsten ras; human cancer; oncogene.

Conflict of interest statement

The authors declare no competing financial interests.


Figure 1
Figure 1. Time line showing the influence of “ras” discovery in human cancer research and the key events related to oncogene history (boxed)
Yearly tabulated numbers of publications between 1969 and 2014 with the keywords “human + carcinogenesis” and one of the following: “oncogene, ” “tumor virus, ” “carcinogen, ” “ras, ” “Kras/K-ras/ki-ras, ” or “src.” The numbers for Kras/K-ras/ki-ras were counted separately for Kras, K-ras, or ki-ras, but overlapping publications were only counted once. Numbers were tabulated from 2005, when the Human Genome Nomenclature Committee updated the KRAS2 (c-ki-ras2) gene symbol to KRAS. Numbers were counted based on the PubMed database (NCBI, NIH) in July 2015.
Figure 2
Figure 2. Comparisons of Ki-SV, Mo-SV, RSV, and the corresponding leukemia viral genomes
A. Genomic structures of Murine leukemia virus (top structure), Kirsten sarcoma virus [17, 72], and Moloney sarcoma virus [141]. B. ALV/tdRSV (avian leukemia virus/transformation defective RSV, the upper structure) and RSV (bottom structure). Leukemia viruses/tdRSV mutant genomes are shown for comparison. Each sarcoma virus figure shows regions covered by sarcoma virus-specific cDNA by an arrow.
Figure 3
Figure 3. Physical maps and comparison of viral and cellular amino acid sequences of Ras isoforms
A. Physical map of Ki-SV and its restriction sites [3, 4, 17, 33, 60]. The positions corresponding to KRAS exons 1, 2, 3, and 4A, and 4B are shown in red and green, respectively, for (1) viral RNA, (2) the linear form DNA with LTRs at both ends, aligned with viral RNA, (3) clone 4 DNA (circular DNA was linearized at BamHI and inserted into plasmid vector) with subclone KBE-2 underneath as the blue thick line, and (4) clone 4(E) DNA (circular DNA was linearized at EcoRI and inserted into a vector). Restriction sites are shown for viral DNA. B. Physical map of Ha-SV DNA Clone H-1 [15, 16, 17, 75, 80]. Circular DNA with LTR was linearized at EcoRI, and the positions corresponding to HRAS exons 1, 2, 3, and 4 (in red) and restriction sites are shown. The sub-clone pHB-11 for heteroduplex analysis is shown with the blue thick line, underneath clone H-1. The scale is in Kb for both Ki-SV DNA and Ha-SV DNA. C. Comparisons of viral and cellular exon 4 amino acid sequences of Ras isoforms and KRAS exon 4B. Amino acid sequences of v-KRAS, v-HRAS and v-BAS, and those corresponding human sequences of exon 4 and NRAS are presented. Viral KRAS exon 4B is the sequence of the corresponding rat sequence inferred from the corresponding viral sequence [33]. Amino acid residues that are different from that of viral KRAS are shown in red or blue, and differences between the human cellular and the viral sequences are shown in green. In viral and cellular KRAS 4B, polylysine residues and serine 181 phosphorylated with PKC are shown with bold letters.
Figure 4
Figure 4. Identification of the viral ras oncogenes and distribution of sub-clones
Cloning of viral genomes and identification of their oncogenes were performed in the laboratories of Tsuchida (v-Kras), Scolnick, (v-Hras), and Aaronson (v-Bas/v-Hras). Subclones containing viral oncogenes (pHiHi-3, and/or pKBE-2 of v-Kras, pBS-9 of v-Hras) were used in the laboratories of Wigler, Cooper, Weinberg, and Levinson/Goeddel. The laboratories of Aaronson and Barbacid used their BALB-MSV clone pHB-1 for HRAS/BAS detection and clone 4(E) and HiHi-3 for KRAS detection. Publications of RAS genes from these eight laboratories are listed as references (indicated in red for HRAS/BAS and in blue for KRAS.
Figure 5
Figure 5. Growth signaling and mutated signal proteins that confer resistance to anti-EGFR-targeted therapy in mCRC
Growth factor stimulation in the normal cell generally proceeds as follows: (i) activation of the receptor by phosphorylation and dimerization, (ii) activation of RAS and PI3K, and then (iii) activation of the RAS effector pathways RAF, PI3K, and RALGDS through binding to RBD of each protein. In mCRC, EGFR copy number was often increased. EGFR-targeted therapy prevents steps (i) and (ii) by using anti-EGFR monoclonal antibodies (mAb) or a tyrosine kinase inhibitor (TKI). An oncogenic driver mutation of the EGFR effector (KRAS, NRAS, or PIK3CA) or the RAS effector (PIK3CA or BRAF) makes cancer patients refractory to EGFR-targeted therapy, while patients with wild-type KRAS/NRAS/PIK3CA/BRAF are mostly sensitive to this therapy. Activated tumor driver proteins are shown as frames with thick lines. Refer to the text for details.

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