K-<i>ras</i> is an essential gene in the mouse with partial functional overlap with N-<i>ras</i>

Johnson, Leisa; Greenbaum, Doron C.; Cichowski, Karen; Mercer, Kim L.; Murphy, Elizabeth; Schmitt, Éric; Bronson, Roderick T.; Umanoff, H; Edelmann, Windfried; Kucherlapati, Raju; Jacks, Tyler

doi:10.1101/gad.11.19.2468

Cited by 490 publications

(422 citation statements)

References 58 publications

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“…Moreover, it is possible that distinct mammalian Ras (H-Ras, K-Ras, N-Ras) proteins and/or Ras mutants (for example, positions 12,13,61) may di er in their ability to recognize and activate downstream targets, resulting in di erential signaling . For example, gene targeting studies indicate an essential role for Kras, but not H-or N-Ras, for normal development in mice (Koera et al, 1997;Johnson et al, 1997). This data, taken together with earlier observations that KRas-4B possesses distinct carboxy terminus modifications (James et al, 1995) and the speci®c association of KRas4B with smg-GDP dissociation stimulator (GEF) (Mizuno et al, 1991), suggests that K-Ras may have speci®c functions in signal transduction not shared by other family members.…”

Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 82%

Increasing complexity of Ras signaling

et al. 1998

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The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

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Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 82%

Increasing complexity of Ras signaling

et al. 1998

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“…All cells use Ras signaling to some extent, so it is not surprising that perturbation in Ras signaling could have developmental consequences. Although all proteins are widely expressed, KRAS is ubiquitously expressed in almost all cell types and shown to be vital for normal mouse development [Johnson et al, 1997]. In contrast, mouse model studies have demonstrated HRAS and NRAS are not as critical [Malumbres and Barbacid, 2003].…”

Section: Discussionmentioning

confidence: 99%

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

Estep

Tidyman

Teitell

et al. 2005

American J of Med Genetics Pt A

166

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Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well‐characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G → A transition in codon 12. Less frequent mutations included 35G → C (codon 12) and 37G → T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G → A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G → C had cardiac arrhythmias whereas one patient with a 37G → T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G → A mutation. Loss of the wild‐type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio‐facio‐cutaneuos (CFC) syndromes, the HRAS coding region was sequenced in a well‐characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. © 2005 Wiley‐Liss, Inc.

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“…In contrast, K-ras knockout mice die at 12.5 days post coitus (p.c.) from severe anemia (Johnson et al, 1997;Koera et al, 1997). Ras isoforms differ with respect to post-translational modifications, subcellular localization and transformation properties (Hingorani and Tuveson, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cooperation of oncogenic K-ras and p53 deficiency in pleomorphic rhabdomyosarcoma development in adult mice

et al. 2006

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Human rhabdomyosarcomas (RMSs) frequently demonstrate genetic alterations in ras and p53. To investigate their possible involvement in the tumorigenesis, we generated a knock-in mouse line with oncogenic K-ras, conditionally expressed by Cre/LoxP system on a background of p53 alteration. Electroporation of Cre expression vector in skeletal muscle tissues resulted in the generation of tumor in adults with tumor incidences of 100% at 10 weeks and 40% at 15 weeks, in p53 À/À and p53 À/ þ backgrounds, respectively. The tumor histology was pleomorphic RMS with characteristic bizarre giant cells, positive for desmin and a-sarcomeric actin and exhibiting remarkable increase in total and phosphorylated extracellular signal-regulated protein kinase (ERK)1 and ERK2. Loss of the wild-type p53 was detected in K-rasG12V-expressed tumors of p53 À/ þ mice. Early lesions 3 weeks after electroporation consisted of proliferating populations of myogenic progenitors, including stem cells positive for ScaI antigen, immature cells positive for desmin and neural cell adhesion molecule-positive myotubes. Thus, cooperation of oncogenic K-ras and p53 deficiency resulted in the development of pleomorphic RMS in adult mice, providing a useful mouse model for further detailed studies.

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K-ras is an essential gene in the mouse with partial functional overlap with N-ras

Cited by 490 publications

References 58 publications

Increasing complexity of Ras signaling

Increasing complexity of Ras signaling

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

Cooperation of oncogenic K-ras and p53 deficiency in pleomorphic rhabdomyosarcoma development in adult mice

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