Molecular genetic analysis of BAX and cyclin D1 genes in patients with malignant glioma

Abdullah, Jafri Malin; Ahmad, Fadzil; Ahmad, Ku Asmarina Ku; Ghazali, Mazira Mohamad; Jaafar, Hasnan; Ideris, Aini; Ali, Abdul Manaf; Omar, Abdul Rahman; Yusoff, Khatijah; Lila, Mohd Azmi Mohd; Othman, Fauziah

doi:10.1179/016164107x158965

Cited by 26 publications

(19 citation statements)

References 26 publications

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“…NF-κB has been implicated in the regulation of glioma cell proliferation through the upregulation of oncogenes, including cyclin D1, cyclin E, and c-myc (50)(51)(52)(53)(54). The present study revealed that overexpression of TMEM16A significantly increased transcription levels of these genes, which may explain why TMEM16A promotes cell proliferation in gliomas.…”

Section: A B a Bsupporting

confidence: 50%

Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway

Liu

Ren

et al. 2014

Molecular Medicine Reports

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Ion channels have been suggested to be important in the development and progression of tumors, however, chloride channels have rarely been analyzed in tumorigenesis. More recently, transmembrane protein with unknown function 16A (TMEM16A), hypothesized to be a candidate calcium‑activated Cl‑ channel, has been found to be overexpressed in a number of tumor types. Although several studies have implicated the overexpression of TMEM16A in certain tumor types, the exact role of TMEM16A in gliomas and the underlying mechanisms in tumorigenesis, remain poorly understood. In the present study, the role of TMEM16A in gliomas and the potential underlying mechanisms were analyzed. TMEM16A was highly abundant in various grades of gliomas and cultured glioma cells. Knockdown of TMEM16A suppressed cell proliferation, migration and invasion. Furthermore, nuclear factor‑κB (NF‑κB) was activated by overexpression of TMEM16A. In addition, TMEM16A regulated the expression of NF‑κB‑mediated genes, including cyclin D1, cyclin E and c‑myc, involved in cell proliferation, and matrix metalloproteinases (MMPs)‑2 and MMP‑9, which are associated with the migration and invasion of glioma cells. Collectively, results of the present study provide evidence for the involvement of TMEM16A in gliomas and the potential mechanism through which TMEM16A promotes glioma formation.

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Section: A B a Bsupporting

confidence: 50%

Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway

Liu

Ren

et al. 2014

Molecular Medicine Reports

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“…Thus although Bax deletion does not directly model a genetic change seen in human medulloblastoma, the principle demonstrated by Bax deletion, that apoptosis is required for treatment sensitivity, remains highly relevant. Moreover, this principle may be generalizable to other cancers, where inactivating frameshift mutations in Bax have been identified, including human colon cancer, gastric cancer and high grade glioma [38–41]. Our data indicate that any mutation or post-translational event that impairs the internal apoptotic pathway can confer treatment resistance.…”

Section: Discussionmentioning

confidence: 53%

Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway

et al. 2016

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While treatments that induce DNA damage are commonly used as anti-cancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiation therapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine if the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that p53 was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies because they retain apoptosis competence.

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“…Thus, pH-dependent impairment of cyclin D1 degradation could result from mutations in the naturally occurring glioma cell lines [34]. However, mutations in the structural gene of cyclin D1 in glioblastomas are very rare events [35], while overexpression of cyclin D1 is reported in more than 50% of astrocytic tumors [36].…”

Section: Discussionmentioning

confidence: 99%

An acidic environment changes cyclin D1 localization and alters colony forming ability in gliomas

et al. 2008

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The human glioma cell lines, U87 and T98G, were evaluated for their ability to survive and form colonies in an acidic environment of pH ext 6.0. In contrast to U87, which showed an 80-90% survival rate, only 40% of T98G cells survived 6 days at pH ext 6.0 and lost their colony forming ability when returned to a normocidic environment. Although both U87 and T98G cells maintain an intracellular pH (pH i ) of 7.0 at pH ext 6.0 and arrest mostly in G1 phase of the cell cycle, only T98G demonstrated a major loss of cyclin D1 that was prevented by the proteasome inhibitor MG132. Colony forming ability was restored by stably transfecting T98G cells with a cyclin D1-expressing plasmid. Both U87 and T98G cells demonstrated increased cytoplasmic localization of cyclin D1 during exposure at pH ext 6.0. Upon prolonged (24 h) incubation at pH ext 6.0, nuclear cyclin D1 was nearly absent in T98G in contrast to U87 cells. Thus, an acidic environment triggers cytoplasmic localization and proteasomal degradation of cyclin D1.

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Molecular genetic analysis of BAX and cyclin D1 genes in patients with malignant glioma

Abstract: These findings suggest that both cyclin D1 and BAX genes alteration are rarely found in brain tumors. However, the alteration might cause a significant effect of the normal protein production and this might contribute to the development of brain tumorigenesis in Malaysian patients.

Cited by 26 publications

References 26 publications

Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway

Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway

Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway

An acidic environment changes cyclin D1 localization and alters colony forming ability in gliomas

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