The impact of TP53 and RAS mutations on cerebellar glioblastomas

Milinkovic, Vedrana; Skender-Gazibara, Milica; Gacic, Emilija Manojlovic; Gazibara, Tatjana; Tanić, Nikola

doi:10.1016/j.yexmp.2014.07.009

Cited by 21 publications

(13 citation statements)

References 26 publications

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“…KRAS which encodes a small GTPase is one of the Ras oncogene family that is involved in numerous cellular signal transductions [46]. As an oncogene, KRAS is implicated in the progression of various tumors including pilocytic astrocytoma [47] and GBM [48]. As suggested by our IHC and RT-PCR, KRAS was upregulated in glioma tissues and cells compared with the controls, and KRAS expression increased as the malignancy degree progressed in gliomas.…”

Section: Discussionmentioning

confidence: 50%

MicroRNA-134 modulates glioma cell U251 proliferation and invasion by targeting KRAS and suppressing the ERK pathway

et al. 2016

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Dysregulated microRNA-134 (miR-134) has been observed in glioma carcinogenesis, and studies suggested that the ERK pathway plays vital roles in glioma cell growth and proliferation. However, the fundamental relationship between miR-134 and the ERK pathway in glioma has not been fully explained. As a result, this study was aimed to explore the underlying functions of miR-134 in human glioma. Intentionally overexpressed or inhibited miR-134 expression resulted from the transfection of miR-134 mimics, or miR-134 inhibitor within glioma cell line U251 was detected using RT-PCR. Both cell counting kit-8 (CCK-8) assays and Transwell assays were carried out to clarify the proliferation and invasion of U251 cells transfected with miR-134 mimics or miR-134 inhibitors. Our findings showed that miR-134 was significantly downexpressed in glioma tissues, and low miR-134 expression was significantly related to high histopathological grades. However, upregulated miR-134 expression restrained the proliferation and invasion of U251 cells in vitro. Kirsten rat sarcoma viral oncogene (KRAS), a vital factor for the ERK pathway, was directly targeted by miR-134 through its binding with the 3'-UTR of KRAS in glioma. Furthermore, KRAS expression exhibited a positive correlation with the activity of the ERK pathway. Overexpression of KRAS without 3'-UTR partly offsets the suppressive effect of miR-134 on glioma progression. Our data also indicated that miR-134 negatively modulated glioma progression and upregulated miR-134 triggered aberrant activation of the ERK pathway by targeting KRAS. Therefore, miR-134 might be considered as a benign therapeutic target of glioma.

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Section: Discussionmentioning

confidence: 50%

MicroRNA-134 modulates glioma cell U251 proliferation and invasion by targeting KRAS and suppressing the ERK pathway

et al. 2016

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“…Activating point-mutations in hot spot codons 12, 13 and 61 of N-ras gene result in protein products that inhibit GTP hydrolysis constitutively, leading to a prolonged growth-promoting event (2). There exists accumulating evidence for the involvement of N-ras in some types of brain tumors, such as glioblastomas, gliomas and neuroblastomas (2)(3)(4), in addition to other cancers such as leukemia, thyroid tumors, melanoma and colorectal carcinoma (5)(6)(7)(8).…”

mentioning

confidence: 99%

Mutation Screening of Her-2, N-ras and Nf1 Genes in Brain Tumor Biopsies

Yapijakis

Αδαμοπούλου

Tasiouka

et al. 2016

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“…Importantly, Y4 mutations in H-Ras (HRas Y4H ) have been reported in cerebellar glioblastomas [48]. H-Ras Y4H tumor variants taken together with our work showing gain-of-function phenotypes upon mutation at Y4 suggest that Y4 phosphorylation is important for maintaining appropriate restriction of Ras activity and that mutation at Y4 evades such inhibition to promote tissue transformation.…”

Section: Plos Geneticsmentioning

confidence: 55%

A conserved, N-terminal tyrosine signal directs Ras for inhibition by Rabex-5

et al. 2020

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Dysregulation of the Ras oncogene in development causes developmental disorders, "Rasopathies," whereas mutational activation or amplification of Ras in differentiated tissues causes cancer. Rabex-5 (also called RabGEF1) inhibits Ras by promoting Ras mono-and di-ubiquitination. We report here that Rabex-5-mediated Ras ubiquitination requires Ras Tyrosine 4 (Y4), a site of known phosphorylation. Ras substitution mutants insensitive to Y4 phosphorylation did not undergo Rabex-5-mediated ubiquitination in cells and exhibited Ras gain-of-function phenotypes in vivo. Ras Y4 phosphomimic substitution increased Rabex-5mediated ubiquitination in cells. Y4 phosphomimic substitution in oncogenic Ras blocked the morphological phenotypes associated with oncogenic Ras in vivo dependent on the presence of Rabex-5. We developed polyclonal antibodies raised against an N-terminal Ras peptide phosphorylated at Y4. These anti-phospho-Y4 antibodies showed dramatic recognition of recombinant wild-type Ras and Ras G12V proteins when incubated with JAK2 or SRC kinases but not of Ras Y4F or Ras Y4F,G12V recombinant proteins suggesting that JAK2 and SRC could promote phosphorylation of Ras proteins at Y4 in vitro. Anti-phospho-Y4 antibodies also showed recognition of Ras G12V protein, but not wild-type Ras, when incubated with EGFR. A role for JAK2, SRC, and EGFR (kinases with well-known roles to activate signaling through Ras), to promote Ras Y4 phosphorylation could represent a feedback mechanism to limit Ras activation and thus establish Ras homeostasis. Notably, rare variants of Ras at Y4 have been found in cerebellar glioblastomas. Therefore, our work identifies a physiologically relevant Ras ubiquitination signal and highlights a requirement for Y4 for Ras inhibition by Rabex-5 to maintain Ras pathway homeostasis and to prevent tissue transformation.

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The impact of TP53 and RAS mutations on cerebellar glioblastomas

Cited by 21 publications

References 26 publications

MicroRNA-134 modulates glioma cell U251 proliferation and invasion by targeting KRAS and suppressing the ERK pathway

MicroRNA-134 modulates glioma cell U251 proliferation and invasion by targeting KRAS and suppressing the ERK pathway

Mutation Screening of Her-2, N-ras and Nf1 Genes in Brain Tumor Biopsies

A conserved, N-terminal tyrosine signal directs Ras for inhibition by Rabex-5

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