Wildtype Kras2 can inhibit lung carcinogenesis in mice

Zhang, Zhongqiu; Wang, Yian; Vikis, Haris G.; Johnson, Leisa; Liu, Gongjie; Li, Jie; Anderson, Marshall W.; Sills, Robert C.; Hong, Hue-Hua L.; Devereux, Theodora R.; Jacks, Tyler; Guan, Kun‐Liang; You, Ming

doi:10.1038/ng721

Cited by 280 publications

(267 citation statements)

References 41 publications

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“…37,38 Spandidos et al 39 observed that the normal Hras allele could have some suppressive role over the Hras oncogene. In fact, it has been shown that wild-type Kras2 itself has tumor suppressor activity over the Kras2 oncogene, 40 and we have shown that the Nras protooncogene can inhibit malignant properties in the presence of its oncogene. 41 All these findings strongly suggest that the normal ras allele could have some suppressive role in the transformation process by the oncogenic allele.…”

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confidence: 76%

Inhibition of Ras oncogenic activity by Ras protooncogenes

Díaz

Lue

Mathews

et al. 2004

Intl Journal of Cancer

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Point mutations in ras genes have been found in a large number and wide variety of human tumors. These oncogenic Ras mutants are locked in an active GTP-bound state that leads to a constitutive and deregulated activation of Ras function. The dogma that ras oncogenes are dominant, whereby the mutation of a single allele in a cell will predispose the host cell to transformation regardless of the presence of the normal allele, is being challenged. We have seen that increasing amounts of Ras protooncogenes are able to inhibit the activity of the N-Ras oncogene in the activation of Elk in NIH 3T3 cells and in the formation of foci. We have been able to determine that the inhibitory effect is by competition between Ras protooncogenes and the N-Ras oncogene that occurs first at the effector level at the membranes, then at the processing level and lastly at the effector level in the cytosol. In addition, coexpression of the N-Ras protooncogene in thymic lymphomas induced by the N-Ras oncogene is associated with increased levels of p107, p130 and cyclin A and decreased levels of Rb. In the present report, we have shown that the N-Ras oncogene is not truly dominant over Ras protooncogenes and their competing activities might be depending on cellular context. Key words: oncogene inhibition; N-Ras; protooncogene; Ras processing; Ras effectors ras genes play an important role in a variety of differentiation processes and signal transduction, including the regulation of cell proliferation, vesicle movement, cell survival, T-cell activation, apoptosis and cytoskeleton. 1,2 The 3 ras genes encode 4 highly related proteins of 21 kd in size that are ubiquitously expressed: N-Ras, H-Ras, K-RasA and K-RasB. 2,3 Ras is synthesized on free ribosomes as a soluble inactive protein that requires several posttranslational modifications in order to reach the cell membranes where it exhibits its biologic activity. These modifications include prenylation, proteolysis, carboxymethylation and palmitoylation. 4 -7 Once activated by ligand-mediated extracellular stimuli, Ras induces the activation of effector molecules to propagate downstream signals in the cytoplasm and nucleus of the cell. Ras effectors preferentially bind to Ras-GTP through the effector domain loop found in amino acids 32-40. There are several different mammalian proteins that have been described as Ras effectors: Raf, phosphatidylinositol 3-kinase (PI3K), Ral GDP dissociation stimulator (RalGDS), members of the Rho family, mitogen-activating protein kinase 1 (MEKK1), Nore1, among others. 2,3,8 Specific point mutations in ras genes at codons 12, 13 and 61 have been found in a large number and wide variety of human tumors. 9 These mutations render Ras as an oncogene since it is constitutively active (in the GTP-bound form), leading to a deregulated activation of Ras function. 2,3,5,9 -11 In order to dissect the effects of the different downstream pathways of Ras, oncogenic mutants in the effector domain of Ras have been characterized. Thus, Ras/V12/E38 binds Raf and not PI3...

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confidence: 76%

Inhibition of Ras oncogenic activity by Ras protooncogenes

Díaz

Lue

Mathews

et al. 2004

Intl Journal of Cancer

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“…We speculate that KLF4 is also a mediator of transforming growth factor-β (TGFβ)-p21 and adenomatosis polyposis coli (APC)-p21 signalling, thereby relaying signals elicited by multiple key tumour-suppressor pathways. 129 . The tumours, which suffer from a KRas mutation, often showed a loss of the remaining wild-type allele.…”

Section: Linking Opposing Forces In Cancermentioning

confidence: 99%

KLF4, p21 and context-dependent opposing forces in cancer

2005

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| Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

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“…A total of 80 Ag protein/lane was loaded on a 15% SDS-PAGE gel and analyzed by Western blotting with anti-ERK antibody or anti-phospho-ERK antibody (Sigma Chemical) as described previously (33).…”

Section: Western Blot Analysis Of Erk Activitymentioning

confidence: 99%

Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-ras and p53

Zhang¹,

Yao²,

Li³

et al. 2005

Molecular Cancer Research

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Synergistic interaction between H-ras and p53 were systematically examined during skin tumorigenesis. Concurrent expression of an activated H-ras gene and a mutant p53 gene was accomplished by crossing p53 Val135/wt mice with TGÁAC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone produced f26% skin tumor incidence, whereas BaP treatment of p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice produced a 75%, 77%, and 100% incidence of skin tumors, respectively. An average of 0.33 tumor per mouse was observed in wild-type (p53 wt/wt Hras wt/wt ) mice, whereas f1.54, 1.96, and 3.08 tumors per mouse were seen in BaP-treated p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice, respectively. The effects on total tumor volume were even more striking with 7-, 48-, and 588-fold increases in tumor volume compared with wild-type (p53 wt/wt Hras wt/wt ) in p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice, respectively. Histopathologically, all tumors from p53 wt/wt Hras wt/wt mice were either papillomas or well-differentiated squamous cell carcinomas, whereas the tumors in p53 wt/wt Hras TGÁAC/wt , p53 Val135/wt Hras wt/wt , and p53 Val135/wt Hras TGÁAC/wt mice were principally squamous cell carcinomas with varying degree of invasiveness. Particularly, tumors in p53 Val135/wt Hras TGÁAC/wt mice exhibited the most rapid growth and the extreme form of tumor invasion. Microarray analysis revealed that dominant-negative p53 (Val 135 ) and activated H-ras affected several cellular processes involved in tumorigenesis possibly through its effects on apoptosis, cell cycle arrest, and Ras-mitogen-activated protein kinase pathways. The present study provides the first in vivo evidence that a germ line p53 mutation and activated H-ras act synergistically to profoundly enhance tumor progression. (Mol Cancer Res 2005;3(10):563 -74)

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Wildtype Kras2 can inhibit lung carcinogenesis in mice

Cited by 280 publications

References 41 publications

Inhibition of Ras oncogenic activity by Ras protooncogenes

Inhibition of Ras oncogenic activity by Ras protooncogenes

KLF4, p21 and context-dependent opposing forces in cancer

Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-ras and p53

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