INK4a/Arf is required for suppression of EGFR/ΔEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma

Lachat, Yan; Diserens, Annie‐Claire; Nozaki, Michimasa; Kobayashi, Hiroyuki; Hamou, Marie‐France; Godard, Sophie; Tribolet, Nicolas de; Hegi, Monika E.

doi:10.1038/sj.onc.1207872

Cited by 9 publications

(6 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As far as we are aware, there are no existing studies into human glioblastomas in the literature which associate this fact to the activation of ERK1/2. In cell lines derived from mouse glioma models, the resistance to down‐regulate the MAPK pathway in the absence of INK4a/ARF was confirmed 40 . For these authors, the deletion of INK4a/ARF appears to keep ERK in its active, phosphorylated state and insensitive to an upstream inhibitor specifically targeting EGFR/ΔEGFR.…”

Section: Discussionmentioning

confidence: 93%

The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFRamplification

López‐Ginés¹,

Gil-Benso²,

Benito³

et al. 2008

Neuropathology

View full text Add to dashboard Cite

The ERK1/2 activated protein kinase (MAPK) pathway is a critical signaling system that mediates ligand-stimulated signals for the induction of cell proliferation, differentiation and survival, involved in malignant transformation. The purpose of this study was to determine the activation of ERK1/2 in this tumor, and to determine the relationship of ERK1/2 activation with the amplification/overexpression of EGFR as well as with 9p21 locus gene alterations, both of which are genetic factors frequently associated with glioblastoma. We used immunohistochemistry and Western blot analysis to analyze the activation of ERK1/2 in 22 patients with glioblastoma, and we studied the amplification/overexpression of EGFR; as well as the molecular alterations in 9p21 locus genes. Positive immunostaining ERK1/2 was observed in 86.4% of the tumors, displaying mainly nuclear immunolocalization; and by immunoblotting, ERK1/2 was activated in 68% of the cases. The 70% of cases with EGFR amplification presented activated ERK1/2. The joint presence of amplified EGFR and alterations in the 9p21 genes was observed in 50% of the cases, whereas the simultaneous occurrence of these two phenomena with the activation of ERK1/2 was observed in 40% of the cases. Our results suggest that the activation of ERK1/2 is implicated in the pathobiology of glioblastoma. This activation of ERK1/2 is probably related in part to the amplification of EGFR as well as to alterations in 9p21 locus genes (homozygous deletion and promoter methylation). However, the activation of ERK1/2 also involves pathways that are independent of the EGFR.

show abstract

Section: Discussionmentioning

confidence: 93%

The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFRamplification

López‐Ginés¹,

Gil-Benso²,

Benito³

et al. 2008

Neuropathology

View full text Add to dashboard Cite

show abstract

“…Our findings demonstrated that ARF regulates MET in both mouse prostate tumors and PCa cells null for PTEN and p53 genes, a frequent event at the advanced stages of human prostate malignancy (34). Differential to its tumor suppressive role in glioma and melanoma (35), ARF regulates functions and transcriptional activation of oncogenic signaling events in nucleus of cancer cells through multiple mechanisms (36). Thus the details in ARF transition from tumor suppressor to promoter deserve further investigation which may link aging to cancer transformation (37).…”

Section: Discussionmentioning

confidence: 99%

Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer

Xie

Fan

et al. 2018

Oncogene

View full text Add to dashboard Cite

Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF in CRPC in vivo Arf deficiency in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phosphory-tyrosine via computational calculation and experimental assay. Thus nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.

show abstract

“…Although the dispensability of INK4A has been described for some nevus cells (Michaloglou et al, 2005), INK4A is discussed as main senescence mediator in human nevi (Bennett, 2003;Gray-Schopfer et al, 2006). Even though the link between oncogenic RAS or B-RAF and downstream senescence inducers in melanocytes is unclear, a connection between mitogen activated protein kinase (MAPK) activation and INK4A or ARF has been reported for other cell lines (Aguirre et al, 2003;Lachat et al, 2004;Michaloglou et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Oncogene activation in melanocytes links reactive oxygen to multinucleated phenotype and senescence

et al. 2008

View full text Add to dashboard Cite

Contrary to malignant melanoma, nevi are a benign form of melanocytic hyperproliferation. They are frequently observed as precursor lesions of melanoma, but they also feature biochemical markers of senescence. In particular, evidence for oncogene-induced melanocyte senescence as natural means to prevent tumorigenesis has been obtained in nevi with mutated B-Raf V600E. Here, we demonstrate that strong oncogenic growth factor receptor signalling drives melanocytes into senescence, whereas weaker signals keep them in the proliferative state. Activation of oncogene-induced senescence also produces multinucleated giant cells, a long known histological feature of nevus cells. The protein levels of the senescence mediators, p53 and pRB, and their upstream activators do not correlate with senescence. However, strong oncogene signalling leads to pronounced reactive oxygen stress, and scavenging of reactive oxygen species (ROS) efficiently prevents the formation of multinucleated cells and senescence. Similarly, expression of oncogenic N-RAS results in ROS generation, DNA damage and the same multinuclear senescent phenotype. Hence, we identified oncogenic signalling-dependent ROS production as critical mediator of the melanocytic multinuclear phenotype and senescence, both of them being hallmarks of human nevus cells.

show abstract

INK4a/Arf is required for suppression of EGFR/ΔEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma

Cited by 9 publications

References 50 publications

The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFRamplification

The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFRamplification

Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer

Oncogene activation in melanocytes links reactive oxygen to multinucleated phenotype and senescence

Contact Info

Product

Resources

About