A role for the p53 pathway in the pathology of meningiomas with NF2 loss

Chang, ZeNan; Guo, Chin-Lin; Ahronowitz, Iris; Stemmer‐Rachamimov, Anat; MacCollin, Mia; Nunes, Fabio P.

doi:10.1007/s11060-008-9721-3

Cited by 20 publications

(22 citation statements)

References 42 publications

(47 reference statements)

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“…Recently, it was demonstrated that other pathways are associated with merlin, including p53/p21 signaling (19–21). There are similarities between merlin and p53, such as that merlin functions as a general tumor suppressor product to multiple cell types as p53 does, and notably, their tumor suppressive functions are associated with cell cycle control (25–27).…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Xue

et al. 2017

Oncology Letters

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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.

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Section: Discussionmentioning

confidence: 99%

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

Chen

Xue

et al. 2017

Oncology Letters

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“…Consistent with our finding, several recent IHC studies of large cohort of human schwannomas and meningiomas that have detected elevated p53 expression in the majority of NF2 tumors (Chen et al, 2014; Pavelin et al, 2014). Moreover, p53 mutations and loss of p16 have both been linked to progression in human meningiomas (Chang et al, 2009; Kim et al, 2014). While it is tempting to speculate that Rac1-ROS-p53-driven checkpoints and senescence programs may also underlie the benign nature of NF2, it needs to be confirmed using disease relevant mouse models.…”

Section: Discussionmentioning

confidence: 99%

Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression

et al. 2016

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SUMMARY Merlin encoded by the Nf2 gene is a bona fide tumor suppressor that has been implicated in regulation of both the Hippo-Yap and the Rac1-Pak1 pathways. Using genetically engineered murine liver models, we show that co-deletion of Rac1 with Nf2 blocks tumor initiation but paradoxically exacerbates hepatomegaly induced by Nf2 loss, which can be suppressed either by treatment with pro-oxidants or by co-deletion of Yap. Our results suggest that while Yap acts as the central driver of proliferation during Nf2 tumorigenesis, Rac1 primarily functions as an inflammation switch by inducing ROS that on one hand induces NFkB signaling and expression of inflammatory cytokines, and on the other activates p53 checkpoint and senescence programs dampening the cyclinD1-pRb-E2F1 pathway. Interestingly, senescence markers are associated with benign NF2 tumors but not with malignant NF2 mutant mesotheliomas, suggesting that senescence may underlie the benign nature of most NF2 tumors.

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“…thus, this study reveals a high degree of concordance in the aberrations of the p14ARF/MDM2/p53 pathway with the development of sporadic vestibular schwannomas. mesothelioma [4,19,20]. Studies on schwannoma development in patients suggest that a third hit in addition to the alteration of the NF2 gene may be necessary for the development of this tumor [18,24,25].…”

Section: Introductionmentioning

confidence: 99%

P14ARF deficiency and its correlation with overexpression of p53/MDM2 in sporadic vestibular schwannomas

Chen

Wang

2014

Eur Arch Otorhinolaryngol

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Recent studies have shed considerable light into schwannomas. To date, only merlin has been identified as a hallmark or pathogenesis of both sporadic and NF2-related schwannomas. Here, we show, by immunoblot and immunohistochemical analyses of 58 sporadic vestibular schwannomas, that upregulation of p53 was observed in 90 % of tumors examined. No p53 mutations were found in 12 % tumors analyzed. Expression of p14ARF was negative in 95 % of tumors, while overexpression of MDM2 was found in all specimens. Aberrant DNA hypermethylation of the p14ARF promoter was observed in three of seven tumors examined (43 %), associated with remarkably decreased mRNA levels. The very high degree of concordance in the aberrations of the p14ARF/MDM2/p53 pathway in this tumor may be considered to be a new player in the pathogenesis of sporadic vestibular schwannomas. Moreover, expression of p21 (waf1) was negative in all tumors, suggesting that the aberration of this pathway is associated with greater attenuation of p21-mediated signals that are critical for growth inhibition. These data are in agreement with the model in RT-4 rat schwannoma cells: i.e., overexpression of ARF was associated with accumulation of p21 expression both at protein and mRNA levels. ShRNA knock-down of p53 expression attenuated p21-mediated increase in cellular arrest in the G1-phase, suggesting that p14ARF regulates p21 protein levels through a p53-dependent pathway. Thus, this study reveals a high degree of concordance in the aberrations of the p14ARF/MDM2/p53 pathway with the development of sporadic vestibular schwannomas.

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A role for the p53 pathway in the pathology of meningiomas with NF2 loss

Cited by 20 publications

References 42 publications

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

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

Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression

P14ARF deficiency and its correlation with overexpression of p53/MDM2 in sporadic vestibular schwannomas

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