AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX–MDM2 complex

Polo, Anna de; Luo, Zhu; Gerarduzzi, Casimiro; Chen, Xiang; Little, John B.; Yuan, Zhi-Min

doi:10.1093/jmcb/mjw045

Cited by 35 publications

(33 citation statements)

References 47 publications

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“…Interestingly, a recent finding showed that AXL suppressed p53 in melanoma through stabilization of the MDMX-MDM2 complex. AXL activation stabilized MDMX via a post-translational modification that involved phosphorylation of MDMX [ 38 ]. Collectively, these data demonstrate that AXL negatively regulates p53 expression by at least two mechanisms: (1) TP53 transcription inhibition, irrespective of p53 mutation status; (2) stabilization of the MDMX-MDM2 complex.…”

Section: Discussionmentioning

confidence: 99%

AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression

Song

Wang

et al. 2020

Cancers

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Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the AXL promoter. Although TP53 mutations are uncommon in mesothelioma, we hypothesized that these tumors might have alternative feedback mechanisms between AXL and p53. In the current report, we investigated AXL regulation of TP53 transcription, expression, and biological function in mesothelioma. AXL expression was stronger in mesothelioma than most of the other tumor types from the TCGA gene expression profile dataset. AXL knockdown by shRNA induced wild-type and mutant p53 expression in mesothelioma cell lines, suggesting that AXL pro-tumorigenic roles result in part from the suppression of p53 function. Likewise, induced AXL inhibited expression of wild type p53 in COS-7 cells and 293T cells. Immunofluorescence staining showed nuclear colocalization of AXL and p53; however, association of AXL and p53 was not demonstrated in immunoprecipitation complexes. The AXL effects on p53 expression resulted from the inhibition of TP53 transcription, as demonstrated by qRT-PCR after AXL silencing and TP53 promotor dual luciferase activity assays. Chromatin immunoprecipitation-qPCR and sequencing showed that AXL bound to the initial 600 bp sequence at the 5′ end of the TP53 promoter. AXL inhibition (shRNA or R428) reduced mesothelioma cell viability, migration, and invasion, whereas TP53 shRNA knockdown attenuated antiproliferative, migration, and invasive effects of AXL silencing or AXL inactivation in these cells. These studies demonstrate a novel feedback regulation loop between AXL and p53, and provide a rationale for mesothelioma therapies targeting AXL/p53 signaling.

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Section: Discussionmentioning

confidence: 99%

AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression

Song

Wang

et al. 2020

Cancers

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“…In melanoma, a reduction of the p53 protein levels is commonly reported [ 3 , 11 ••, 12 ]. The downregulation of TP53 gene may be due to several mechanisms [ 62 – 64 ]: inactivation of p14 CDKN2A causing MDM2 overexpression, or increased stability of MDM2-4 proteins induced by activation of the receptor tyrosine kinase AXL, or TP53 gene silencing through genetic changes (mostly, mutations) or epigenetic deregulations (Fig. 1 ).…”

Section: Tp53 Genementioning

confidence: 99%

Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches

et al. 2018

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Purpose of ReviewConventional clinico-pathological features in melanoma patients should be integrated with new molecular diagnostic, predictive, and prognostic factors coming from the expanding genomic profiles. Cutaneous melanoma (CM), even differing in biological behavior according to sun-exposure levels on the skin areas where it arises, is molecularly heterogeneous. The next-generation sequencing (NGS) approaches are providing data on mutation landscapes in driver genes that may account for distinct pathogenetic mechanisms and pathways. The purpose was to group and classify all somatic driver mutations observed in the main NGS-based studies.Recent FindingsWhole exome and whole genome sequencing approaches have provided data on spectrum and distribution of genetic and genomic alterations as well as allowed to discover new cancer genes underlying CM pathogenesis.SummaryAfter evaluating the mutational status in a cohort of 686 CM cases from the most representative NGS studies, three molecular CM subtypes were proposed: BRAFmut, RASmut, and non-BRAFmut/non-RASmut.

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“…In fact, in these cells miR-18b expression is frequently downmodulated by hypermethylation; MDM2 is a molecular target of miR-18b, and the downmodulation of this miR in melanoma cells is responsible for MDM2 upmodulation, with consequent p53 inactivation [ 84 ]. Another mechanism stimulating MDM2 expression in melanoma cells is related to AXL receptor signaling [ 85 ].…”

Section: Molecular Abnormalitiesmentioning

confidence: 99%

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

Testa

Castelli

2017

Medical Sciences

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Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

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AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX–MDM2 complex

Cited by 35 publications

References 47 publications

AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression

AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression

Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

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