AXL regulates mesothelioma proliferation and invasiveness

Wb, Ou; Jm, Corson; Dl, Flynn; Lü, Wei; Wise, S.; Bueno, Raphael; Dj, Sugarbaker; Ja, Fletcher

doi:10.1038/onc.2010.555

Cited by 83 publications

(86 citation statements)

References 35 publications

(42 reference statements)

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“…Axl is known to be involved in promoting the growth and movement of cells. 37,39,43,44,[47][48][49] Therefore, we tested whether mutant p53-induced enhancement of growth and motility has any relationship with the fact that mutant p53 up-regulates the expression of Axl. We used the lung cancer cell line H1048 expressing a mutant p53 (-R273C) for testing its growth rate and motility as described in Materials and Methods.…”

Section: Resultsmentioning

confidence: 99%

“…We analyzed mutant p53-induced genes for the overrepresentation of genes that contain putative p63 binding sites. The Axl gene was selected for further study based on the presence of a p63 binding site, its known role in oncogenesis, 34,40,43,46,47 and its potential role in mutant p53 GOF activities. We first verified the microarray data by performing RT-qPCR analysis of the Axl mRNA, confirming induction by mutant p53.…”

Section: Resultsmentioning

confidence: 99%

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Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl

et al. 2012

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Abstractp53 mutations are present in up to 70% of lung cancer. Cancer cells with p53 mutations, in general, grow more aggressively than those with wildtype p53 or no p53. Expression of tumor-derived mutant p53 in cells leads to up-regulated expression of genes that may affect cell growth and oncogenesis. In our study of this aggressive phenotype, we have investigated the receptor protein tyrosine kinase Axl, which is up-regulated by p53 mutants at both RNA and protein levels in H1299 lung cancer cells expressing mutants p53-R175H, -R273H, and -D281G. Knockdown of endogenous mutant p53 levels in human lung cancer cells H1048 (p53-R273C) and H1437 (p53-R267P) led to a reduction in the level of Axl as well. This effect on Axl expression is refractory to the mutations at positions 22 and 23 of p53, suggesting that p53's transactivation domain may not play a critical role in the up-regulation of Axl gene expression. Chromatin immunoprecipitation (ChIP) assays carried out with acetylated histone antibodies demonstrated induced histone acetylation on the Axl promoter region by mutant p53. Direct mutant p53 nucleation on the Axl promoter was demonstrated by ChIP assays using antibodies against p53. The Axl promoter has a p53/p63 binding site, which however is not required for mutant p53-mediated transactivation. Knockdown of Axl by Axl-specific RNAi caused a reduction of gain-of-function (GOF) activities, reducing the cell growth rate and motility rate in lung cancer cells expressing mutant p53. This indicates that for lung cancer cell lines with mutant p53, GOF activities are mediated in part through Axl.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl

et al. 2012

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“…Although the physiological substrates of CRL4 DCAF1 have not yet been identified, gene expression analysis suggests that CRL4 DCAF1 regulates a broad gene expression programme, consisting of more than 1,000 genes [35]. CRL4 DCAF1 could exert this effect by [111], seems to be inhibited at the tran- [111], seems to be inhibited at the tran-, seems to be inhibited at the transcriptional level by Merlin expression as well as DCAF1 knockdown [35]. Irrespective of the specific mechanism by which CRL4 DCAF1 regulates gene expression, the breadth of the oncogenic gene expression programme it induces and the identity of some of the genes regulated suggest that Merlin could suppress several mitogenic signalling pathways by inhibiting CRL4 DCAF1 .…”

Section: Nuclear Inhibition Of Crl4 Dcaf1mentioning

confidence: 99%

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

et al. 2012

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Inhibition of proliferation by cell-to-cell contact is essential for tissue organization, and its disruption contributes to tumorigenesis. The FERM domain protein Merlin, encoded by the NF2 tumour suppressor gene, is an important mediator of contact inhibition. Merlin was thought to inhibit mitogenic signalling and activate the Hippo pathway by interacting with diverse target-effectors at or near the plasma membrane. However, recent studies highlight that Merlin pleiotropically affects signalling by migrating into the nucleus and inducing a growth-suppressive programme of gene expression through its direct inhibition of the CRL4 DCAF1 E3 ubiquitin ligase. In addition, Merlin promotes the establishment of epithelial adhesion and polarity by recruiting Par3 and aPKC to E-cadherin-dependent junctions, and by ensuring the assembly of tight junctions. These recent advances suggest that Merlin acts at the cell cortex and in the nucleus in a similar, albeit antithetic, manner to the oncogene β-catenin.

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“…Moreover, ectopic expression of AXL has been shown to confer resistance to EGF receptor therapy in lung cancer (10,11). Multiple studies have demonstrated AXL and MER function in survival, invasion, and metastasis in a variety of tumors (12)(13)(14)(15); thus, attention has focused on the pharmacologic targeting of AXL and MER in cancer. Axl and Mer share structural homology in the kinase domain with other tyrosine kinases, including conserved molecular interactions with ATP; however, several unique features of the active site allow for selective inhibition (16), and small-molecule inhibitors as well as biologics are in preclinical development (6,(16)(17)(18)(19).…”

mentioning

confidence: 99%

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

Bosurgi¹,

Bernink²,

Cuevas³

et al. 2013

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

126

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The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling characteristic of multiple cancer hallmarks. These contrasting oncogenic and anti-inflammatory functions of Axl and Mer posit a potential paradox in terms of anticancer therapy. Here we demonstrate that azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced inflammationassociated cancer is exacerbated in mice lacking Axl and Mer. Ablation of Axl and Mer signaling is associated with increased production of proinflammatory cytokines and failure to clear apoptotic neutrophils in the intestinal lamina propria, thereby favoring a tumor-promoting environment. Interestingly, loss of these genes in the hematopoietic compartment is not associated with increased colitis. Axl and Mer are expressed in radioresistant intestinal macrophages, and the loss of these genes is associated with an increased inflammatory signature in this compartment. Our results raise the possibility of potential adverse effects of systemic anticancer therapies with Axl and Mer inhibitors, and underscore the importance of understanding their tissue and cell type-specific functions in cancer.T he proto-oncogenes AXL and MER were first cloned from chronic myelogenous and lymphoblastic leukemia cells (1-3). Increased expression of AXL has been reported in lung, breast, ovarian, gastric, pancreatic, and prostate cancers; leukemias and lymphomas; melanoma; and glioblastoma multiforme (4, 5). Increased MER expression is associated with leukemias, lymphomas, melanoma, rhabdomyosarcomas, and gastric and prostate cancers (4-6). AXL and MER expression also has been directly correlated with poor prognosis in cancer (6-9). Moreover, ectopic expression of AXL has been shown to confer resistance to EGF receptor therapy in lung cancer (10, 11). Multiple studies have demonstrated AXL and MER function in survival, invasion, and metastasis in a variety of tumors (12-15); thus, attention has focused on the pharmacologic targeting of AXL and MER in cancer. Axl and Mer share structural homology in the kinase domain with other tyrosine kinases, including conserved molecular interactions with ATP; however, several unique features of the active site allow for selective inhibition (16), and small-molecule inhibitors as well as biologics are in preclinical development (6,(16)(17)(18)(19).Axl and Mer are associated with another distinct feature of cancer-inflammation. Tumor-promoting inflammation has been described as an enabling characteristic that promotes the acquisition of cancer hallmarks and orchestrates tumor progression (20). Chronic inflammation increases the risk of colorectal canc...

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AXL regulates mesothelioma proliferation and invasiveness

Cited by 83 publications

References 35 publications

Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl

Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer

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