Age dependent phosphorylation and deregulation of p53 in human vestibular schwannomas

Abstract

Tumor-specific alterations at the p53 gene locus in 30 human vestibular schwannomas (VS) comprising 10 confirmed NF2 cases and 20 sporadic cases were analyzed. We found loss of heterozygosity (LOH) at the first intron of the p53 gene locus in 54% of the informative cases. This is the first report showing LOH at the p53 gene locus in a significant number of human VS and both sporadic and NF2 cases show the LOH event. Increased levels of normal size p53 mRNA and p53 protein were found in all the tumors analyzed. Thus p53 appears to be deregulated in all the tumors suggesting that p53 alterations may be associated with tumor progression in VS. There was a negative significant correlation of patients' age and percentage of Ser 392 phosphorylated p53 protein. The tumor samples obtained from younger patients of 35 yr and below showed higher percentage of Ser 392 phosphorylated p53 protein compared to the tumors of older patients. The increased percentage of Ser 392 phosphorylated p53 protein indicates that it could be involved in the acceleration of tumor growth in the younger patients. Our results suggest that age dependent phosphorylation of p53 protein and deregulation of p53 gene has a role in the development of human vestibular schwannomas.

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

“…Although p53 mutations are the most common molecular lesions in human cancer, overexpression of p53 but no p53 mutations are reported in human schwannomas [5]. these are comparable to our observations in this study that schwannoma tumors lacking p14ARF exhibited relatively high levels of p53 but no p53 mutations (Figs.…”

Preclinical validation of anti‐nuclear factor‐kappa B therapy to inhibit human vestibular schwannoma growth

“…Of the 622 articles identified, 19 met our inclusion criteria (Aarhus et al, 2010;Archibald et al, 2010;Bian et al, 2005; Cay e- Thomasen et al, 2010;Cioffi et al, 2010;Dayalan et al, 2006;Doherty et al, 2008;Kramer et al, 2010;Lassaletta et al, 2009;O'Reilly et al, 2004;Patel et al, 2008;Plotkin et al, 2009;Sawaya and Highsmith, 1988;Saydam et al, 2011;Seol et al, 2005;Stankovic et al, 2009;Szeremeta et al, 1995;Thomas et al, 2005;Welling et al, 2002), generating 221 molecules eligible for network analysis: 162 overexpressed and 59 underexpressed molecules in sporadic VS. IPA generated a total of 19 networks. Supplementary Table S1 shows the hubs of the top 14 networks.…”

BAY 61-3606, CDKi, and Sodium Butyrate Treatments Modulate p53 Protein Level and Its Site-Specific Phosphorylation in Human Vestibular Schwannomas In Vitro

“…It is then distributed to other labs for research purpose only. The cells were propagated at 37 ∘ C with 5% CO 2 in a 95% humidified incubator as described previously [13,14]. The cells were fed with DMEM (Sigma-Aldrich, St. Louis, MO, USA) containing 10% fetal bovine serum (FBS) and propagated to approximately 70 to 80% confluency in 100 mm cell culture dishes in presence of penicillin (100 U/mL) and streptomycin (100 g/mL).…”

“…Ten of these phosphorylations occur in the amino terminal trans-activation domain, 1 occurs in the tetramerisation domain, 1 occurs in the proline-rich domain, 3 occur in the DNA binding domain, and 3 occur in the carboxy terminal regulatory domain [10]. The site-specific p53 phosphorylation is one of the important PTMs which affects its many functions including its function as a tumor suppressor [10,[13][14][15][16][17]. The current study is undertaken to evaluate the effect of small molecules on the p53 phosphorylation and its correlation to VS tumor cell survival in vitro.…”