TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity

Liang, Mei‐Chih; Ma, Jingdong; Chen, Liang; Kozlowski, Piotr; Qin, Wei; Li, D.; Goto, June; Shimamura, Takeshi; Hayes, D. Neil; Meyerson, Matthew; Kwiatkowski, D. J.; Wong, Kwok-Kin

doi:10.1038/onc.2009.452

Cited by 49 publications

(56 citation statements)

References 42 publications

(80 reference statements)

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“…These findings add to a growing list of somatic mutations that cooperate with mutant Kras to promote lung adenocarcinoma development in mice (19,22,28,33,52). However, Map2k4 inactivation mitigates carcinogen-induced skin tumors in the same mouse strain (MKK4 L/L ) used in this study (12), which may reflect tissue-specific roles of MKK4, differential signaling by mutant Ras family members (Kras and Hras in lung and skin carcinomas, respectively), or other factors.…”

Section: Discussionmentioning

confidence: 48%

“…The subjection of Kras-mutant mice to a second oncogenic event leads to lung adenocarcinomas that arise earlier, grow faster, and metastasize widely. Proven cooperative events include inactivating mutations in tumor suppressor genes (Tsc1, Lkb1, or Pten), overexpression of Hif2␣, and introduction of Tp53 R172H , a mutation that confers metastatic potential to tumors in mice and is found in patients with Li-Fraumeni syndrome and sporadic lung cancer (5,19,28,33,52). However, the incidence of metastatic disease in these double-mutant mice is, in many cases, far less than 100%, suggesting that additional genetic events are necessary for such an outcome.…”

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confidence: 99%

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Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

Ahn

Yang

Gibbons

et al. 2011

Molecular and Cellular Biology

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MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas that develop in mice owing to expression of mutant Kras and Tp53. Conditional Map2k4 inactivation in the bronchial epithelium of mice had no discernible effect alone but increased the multiplicity and accelerated the growth of incipient lung neoplasias induced by oncogenic Kras. MKK4 suppressed the invasion and metastasis of Kras-Tp53-mutant lung adenocarcinoma cells. MKK4 deficiency increased peroxisomal proliferator-activated receptor ␥2 (PPAR␥2) expression through noncanonical MKK4 substrates, and PPAR␥2 enhanced tumor cell invasion. We conclude that Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing PPAR␥2 levels.

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Section: Discussionmentioning

confidence: 48%

mentioning

confidence: 99%

Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

Ahn

Yang

Gibbons

et al. 2011

Molecular and Cellular Biology

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“…For MLPA analysis, gDNA from P0 brains was isolated using a DNA isolation kit (Qiagen). MLPA analysis to determine the gene recombination ratio at the Tsc1 c allele was performed as indicated previously (58).…”

Section: Methodsmentioning

confidence: 99%

Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex

Goto

Talos

Klein

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

155

133

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Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding in TSC is the cerebral cortical tuber and its unique constituent, giant cells. However, an animal model that replicates giant cells has not yet been described. Here, we report that mosaic induction of Tsc1 loss in neural progenitor cells in Tsc1 cc Nestin-rtTA + TetOp-cre + embryos by doxycycline leads to multiple neurological symptoms, including severe epilepsy and premature death. Strikingly, Tsc1-null neural progenitor cells develop into highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated giant cells had multiple signs of organelle dysfunction, including markedly increased mitochondria, aberrant lysosomes, and elevated cellular stress. We found similar vacuolated giant cells in human tuber specimens. Postnatal rapamycin treatment completely reversed these phenotypes and rescued the mutants from epilepsy and premature death, despite prenatal onset of Tsc1 loss and mTOR complex 1 activation in the developing brain. This TSC brain model provides insights into the pathogenesis and organelle dysfunction of giant cells, as well as epilepsy control in patients with TSC.

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“…Loss of LKB1 contributes to more aggressive phenotype with limited therapeutic options (8,9,33,34). Recently, increasing efforts have been made to identify a powerful therapeutic strategy for Lkb1-deficient lung cancer.…”

Section: G12dmentioning

confidence: 99%

YAP Promotes Malignant Progression of Lkb1-Deficient Lung Adenocarcinoma through Downstream Regulation of Survivin

Zhang

Gao

et al. 2015

Cancer Research

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The serine/threonine kinase LKB1 is a well-characterized tumor suppressor that governs diverse cellular processes, including growth, polarity, and metabolism. Somatic-inactivating mutations in LKB1 are observed in about 15% to 30% of non-small cell lung cancers (NSCLC). LKB1 inactivation confers lung adenocarcinomas (ADC) with malignant features that remain refractory to therapeutic intervention. YAP activation has been linked to LKB1 deficiency, but the role of YAP in lung ADC formation and progression is uncertain. In this study, we showed that ectopic expression of YAP in type II alveolar epithelial cells led to hyperplasia in mouse lungs. YAP overexpression in the KrasG12D lung cancer mouse model accelerated lung ADC progression. Conversely, YAP deletion dramatically delayed the progression of lung ADC in LKB1-deficient Kras G12D mice. Mechanistic studies identified the antiapoptotic oncoprotein survivin as the downstream mediator of YAP responsible for promoting malignant progression of LKB1-deficient lung ADC. Collectively, our findings identify YAP as an important contributor to lung cancer progression, rationalizing YAP inhibition in the context of LKB1 deficiency as a therapeutic strategy to treat lung ADC.Cancer Res; 75(21); 4450-7. Ó2015 AACR.

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TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity

Cited by 49 publications

References 42 publications

Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

Map2k4 Functions as a Tumor Suppressor in Lung Adenocarcinoma and Inhibits Tumor Cell Invasion by Decreasing Peroxisome Proliferator-Activated Receptor γ2 Expression

Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex

YAP Promotes Malignant Progression of Lkb1-Deficient Lung Adenocarcinoma through Downstream Regulation of Survivin

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