Involvement of p21 (waf1) in merlin deficient sporadic vestibular schwannomas

Wu, Hao; Chen, Y.; Wang, Z.Y.; Li, W.; Li, J.Q.; Zhang, L.; Lu, Yi

doi:10.1016/j.neuroscience.2010.06.051

Cited by 11 publications

(19 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All the untreated VS samples had significantly low level of p21 cip1/waf1 protein (Figure 5a–c) and it correlates to the previous report on loss of its expression in VS tumours [27]. The increased p21 cip1/waf1 level by Na-Bu and BAY 61-3606 treatments can be attributed to induction of TGF-β1 (Figures 4a–c and 5a–c).…”

Section: Discussionsupporting

confidence: 87%

ecancermedicalscience

Mitra

Bhagavatula²,

Gope³

View full text Add to dashboard Cite

Background:Disrupted kinase and signaling pathways are found in many human cancers and they are implicated in carcinogenesis. Therefore, kinases have been important targets for the development of cancer therapeutics. Human vestibular schwannomas (VS) are the third most common intracranial tumours which occur in the vestibular branch of VIIIth cranial nerve. Sodium butyrate (Na-Bu) is a potent histone deacetylase inhibitor (HDACi) and with therapeutic efficacy. Spleen tyrosine kinase (Syk) has been implicated in many immunological consequences and is a putative target for cancer treatment.Aims and objectives:The present study was undertaken in order to evaluate the effect Na-Bu, 2,4-Diamino-5-oxo-pyrimidine hydrochloride (CDKi), a broad spectrum kinase inhibitor and BAY 61-3606 (Syk inhibitor) on the survival of VS tumour tissues in vitro and their possible effects on cell survival/death and levels of a few key proteins in the treated cells as compared to the untreated cells.Materials and methodsFresh tumour tissues were collected randomly from 16 patients with sporadic, VS tumours, minced into pieces and maintained in primary cultures. Twenty four hours later these cells were exposed to Na-Bu, BAY 61-3606 or CDKi. Forty eight hours after exposure, the tissue lysates were analysed by western blotting for expression of pRb and other proteins involved in cell survival/death.Summary and significance of the findings:The tissue samples used were positive for S100A protein, the maker for schwann cells confirming the VS tumour samples. The three individual treatments led to morphological change, DNA fragmentation and cell death and significantly reduced level of total and phosphorylated forms of pRb protein and drastically reduced EGF-R protein. These treatments also modulated levels of other proteins involved in cell survival/death such as PI3K, Caspase 3, TGF-β1, JNK, ASK1, Shh, NF-κB, p21cip1/waf1. The Untreated cells had uncleaved PARP-1 protein and the treated cells had cleaved PARP-1. The results show that the observed cell death in treated cells perhaps is mediated by modulation of the levels and processing of certain key proteins. The possible development of these components as therapeutics is discussed.

show abstract

Section: Discussionsupporting

confidence: 87%

ecancermedicalscience

Mitra

Bhagavatula²,

Gope³

View full text Add to dashboard Cite

show abstract

“…An ever-increasing breadth of evidence has proposed that tumor protein p53 (TP53) , a classical tumor suppressor gene, is associated with NF2 in several genetic and protein studies (18–21). Loss of functional NF2-TP53 -double mutant mice exhibited an increased predisposal to neoplasms compared with each of the single mutant mice (18).…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…P21 (waf1) is an important cellular checkpoint molecule for the inhibition of activities of a range of cyclin-CDKs [7]. Our previous study in vestibular schwannoma indicated that merlin exerts its antiproliferative effect, at least in part, by maintaining p21 expression, and loss of p21 is a prominent feature of merlin-deficient schwannomas [26].…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Wang

2014

Eur Arch Otorhinolaryngol

View full text Add to dashboard Cite

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.

show abstract

Involvement of p21 (waf1) in merlin deficient sporadic vestibular schwannomas

Cited by 11 publications

References 26 publications

ecancermedicalscience

ecancermedicalscience

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

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

Contact Info

Product

Resources

About