Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene

Meuwissen, Roger; Linn, Sabine C.; Valk, Martin van der; Mooi, Wolter J.; Berns, Anton

doi:10.1038/sj.onc.1204837

Cited by 186 publications

(146 citation statements)

References 45 publications

(42 reference statements)

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“…using either adenoviral Cre or transgenic systems to induce the expression of mutant K-ras within the lung (Fisher et al, 2001;Jackson et al, 2001;Johnson et al, 2001;Meuwissen et al, 2001). However, the robust nature of inflammation in the CC10-Cre/LSL-K-ras G12D model and the high concentrations of chemotactic substances elaborated by these tumor cells have not been previously reported and therefore provide a unique opportunity to dissect the means by which inflammatory cells are recruited to sites of tumorigenesis, and the roles that these cells play in tumor progression vs suppression.…”

Section: Discussionmentioning

confidence: 99%

K-ras activation generates an inflammatory response in lung tumors

et al. 2005

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Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras G12D alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.

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Section: Discussionmentioning

confidence: 99%

K-ras activation generates an inflammatory response in lung tumors

et al. 2005

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“…This tetracycline transactivator system has recently been utilized for introducing conditional expression of FGF family members into Clara and type II cells (270). Future studies employing these approaches in combination with the Cre-lox recombinase system (158,159,218) to regulate specific LPP isoform expression spatially and temporally hold considerable promise for investigating physiological functions of these lipid phosphohydrolases in lung.…”

Section: Final Considerationsmentioning

confidence: 99%

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

Nanjundan

Possmayer

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The lung contains two distinct forms of phosphatidic acid phosphatase (PAP). PAP1 is a cytosolic enzyme that is activated through fatty acid-induced translocation to the endoplasmic reticulum, where it converts phosphatidic acid (PA) to diacylglycerol (DAG) for the biosynthesis of phospholipids and neutral lipids. PAP1 is Mg2+ dependent and sulfhydryl reagent sensitive. PAP2 is a six-transmembrane-domain integral protein localized to the plasma membrane. Because PAP2 degrades sphingosine-1-phosphate (S1P) and ceramide-1-phosphate in addition to PA and lyso-PA, it has been renamed lipid phosphate phosphohydrolase (LPP). LPP is Mg2+independent and sulfhydryl reagent insensitive. This review describes LPP isoforms found in the lung and their location in signaling platforms (rafts/caveolae). Pulmonary LPPs likely function in the phospholipase D pathway, thereby controlling surfactant secretion. Through lowering the levels of lyso-PA and S1P, which serve as agonists for endothelial differentiation gene receptors, LPPs regulate cell division, differentiation, apoptosis, and mobility. LPP activity could also influence transdifferentiation of alveolar type II to type I cells. It is considered likely that these lipid phosphohydrolases have critical roles in lung morphogenesis and in acute lung injury and repair.

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“…K-ras mutation has been detected in 70-90% of pancreatic carcinomas, 50% of colorectal carcinomas, and 20-50% of lung carcinomas (Forrester et al, 1987;Rodenhuis et al, 1987;Bos, 1989;Hruban et al, 1993). In tumor cells carrying K-ras mutation, the presence of oncogenic K-Ras is necessary for maintenance of the transformed phenotype (Fisher et al, 2001;Johnson et al, 2001;Meuwissen et al, 2001). Given this, several techniques, such as techniques using farnesyl-transferase inhibitors, antisense oligonucleotides, ribozymes or siRNAs, have been developed to inhibit the activity of Ras (Adjei, 2001;Andreyev et al, 2001;Brummelkamp et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to activation by point mutations, K-ras has been found to be amplified or overexpressed in some cancers (Galiana et al, 1995). Studies using genetically engineered mice have shown that the presence of oncogenic K-ras is not only essential for the initiation of tumorigenesis but also necessary for maintenance of the transformed state (Fisher et al, 2001;Johnson et al, 2001;Meuwissen et al, 2001). Thus, K-Ras is a crucial molecular target in therapeutic strategies to inhibit tumor cell growth.…”

Section: Introductionmentioning

confidence: 99%

Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene

et al. 2005

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Gain-of-function mutation of the K-ras gene is one of the most common genetic changes in human tumors. In tumors carrying K-ras mutation, the presence of oncogenic K-Ras is necessary for maintenance of the transformed phenotype. ESXR1 is a human paired-like homeodomain-containing protein expressed primarily in the testis. In cells, the 65-kDa full-length ESXR1 protein is proteolytically processed into an N-terminal 45-kDa fragment containing the homeodomain, which localizes exclusively within the nucleus, and a C-terminal 20-kDa fragment consisting of a proline-rich repeat region, which is located in the cytoplasm. In this work, we demonstrated that the N-terminal ESXR1 fragment specifically recognizes the TAATNNNATTA P3 consensus sequence for the paired-like homeodomain and functions as a sequencespecific transcriptional repressor. We also showed that the N-terminal ESXR1 fragment binds to the TAATGTTAT TA sequence present within the first intron of the human K-ras gene and inhibits its expression at both mRNA and protein levels. Ectopic expression of the N-terminal ESXR1 fragment in human carcinoma cells that carry mutated K-ras reduces the level of K-Ras and thereby inhibits the tumor cell proliferation. Identification of ESXR1 as a transcriptional repressor of K-ras has an important implication for the development of cancer therapy that inhibits oncogenic K-Ras expression.

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Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene

Cited by 186 publications

References 45 publications

K-ras activation generates an inflammatory response in lung tumors

K-ras activation generates an inflammatory response in lung tumors

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene

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