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P53 performs an essential role in mediating the oncogenic stimulus triggered by loss of expression of neurofibromatosis type 2 during in vitro tumor progression.

ABSTRACT: The loss of the tumor suppressor neurofibromatosis type 2 gene, encoding merlin, has been considered to be a fundamental event during the malignant progression of various cell types. However, a consensus for the mainstream mechanism, by which merlin deficiency contributes to uncontrolled cellular proliferation, has not been reached. The present study aimed to determine whether silencing of merlin using lentivirus-based short hairpin RNA potentiates cellular proliferation and cell cycle progression in human colon carcinoma HCT116 cell lines, expressing p53. The present results demonstrated that merlin knockdown contributed to cellular proliferation and G1/S cell cycle progression to a greater extent in HCT116 cells wide-type for p53 (p53wt) compared with p53-null (p53-/-) cells. This was supported by overexpression experiments which demonstrated a significant inhibitory effect of excess merlin on cellular proliferation only in HCT116 p53wt cells. In order to investigate the underlying mechanisms of action, the expression of p53-involved G1/S transition genes was evaluated by western blot analysis. For HCT116 p53wt cells, merlin loss suppressed p53 expression, and therefore the dysregulation of cell cycle regulatory proteins, including p21, cyclin D1/cyclin-dependent kinase (CDK)4 and cyclin E1/CDK2 complexes. However, merlin knockdowns had no impact on the expression of any of the aforementioned molecules in p53-/- cells, indicating that lack of merlin resulted in G1/S cell cycle progression, and thereby uncontrolled cellular proliferation mainly via the regulation of p53-mediated pathways. Taken together, it was proposed that p53 performs an essential role in mediating the oncogenic stimulus triggered by merlin loss, and p53 is a molecule that should be investigated for its potential in targeted drug therapy for merlin-deficient malignancies.

SUBMITTER: Li X

PROVIDER: S-EPMC5530008 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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p53 performs an essential role in mediating the oncogenic stimulus triggered by loss of expression of neurofibromatosis type 2 during <i>in vitro</i> tumor progression.

Li Xiye X Chen Hongsai H Xue Lu L Pang Xiuhong X Zhang Xiaoman X Zhu Zhengjie Z Zhu Weidong W Wang Zhaoyan Z Wu Hao H

Oncology letters 20170621 2

The loss of the tumor suppressor <i>neurofibromatosis type 2</i> gene, encoding merlin, has been considered to be a fundamental event during the malignant progression of various cell types. However, a consensus for the mainstream mechanism, by which merlin deficiency contributes to uncontrolled cellular proliferation, has not been reached. The present study aimed to determine whether silencing of merlin using lentivirus-based short hairpin RNA potentiates cellular proliferation and cell cycle pr ...[more]

PMID: 28789444

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Project description:PURPOSE: The goal of this work was to (i) determine patterns of progression in glaucomatous visual field loss, (ii) compare the detection rate of progression between locally condensed stimulus arrangements and conventional 6 degrees x 6 degrees grid, and (iii) assess the individual frequency distribution of test locations exhibiting a local event (i.e., an abrupt local deterioration of differential luminance sensitivity (DLS) by more than -10 dB between any two examinations). METHODS: The visual function of 41 glaucomatous eyes of 41 patients (16 females, 25 males, 37 to 75 years old) was examined with automated static perimetry (Tuebingen Computer Campimeter or Octopus 101-Perimeter). Stimuli were added to locally enhance the spatial resolution in suspicious regions of the visual field. The minimum follow-up was four subsequent sessions with a minimum of 2-month (median 6-month) intervals between each session. Progression was identified using a modified pointwise linear regression (PLR) method and a modified Katz criterion. The presence of events was assessed in all progressive visual fields. RESULTS: Eleven eyes (27%) showed progression over the study period (median 2.5 years, range 1.3-8.6 years). Six (55%) of these had combined progression in depth and size and five eyes (45%) progressed in depth only. Progression in size conformed always to the nerve fiber course. Seven out of 11 (64%) of the progressive scotomata detected by spatially condensed grids would have been missed by the conventional 6 degrees x 6 degrees grid. At least one event occurred in 64% of all progressive eyes. Five of 11 (46%) progressive eyes showed a cluster of events. CONCLUSIONS: The most common pattern of progression in glaucomatous visual fields is combined progression in depth and size of an existing scotoma. Applying individually condensed test grids remarkably enhances the detection rate of glaucomatous visual field deterioration (at the expense of an increased examination time) compared to conventional stimulus arrangements.

Dataset Information

P53 performs an essential role in mediating the oncogenic stimulus triggered by loss of expression of neurofibromatosis type 2 during in vitro tumor progression.

Publications

p53 performs an essential role in mediating the oncogenic stimulus triggered by loss of expression of neurofibromatosis type 2 during <i>in vitro</i> tumor progression.

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