Loss of heterozygosity of the p53 gene and deregulated expression of its mRNA and protein in human brain tumors

Abstract

Tumor-specific alterations at the p53 gene locus were analyzed in 40 human brain tumor samples. Gliomas were more prevalent in young males and meningiomas in old females. Structural changes at the intron 1 region of the p53 gene were analyzed in these tumors by Southern blotting. Among the 40 tumors, 33 were informative and 21 of these (63.6%) informative cases showed loss of heterozygosity (LOH). This is the first report showing LOH at the intron 1 region of p53 gene in human brain tumors. The level of p53 mRNA, p53 protein and Ser 392 phosphorylated p53 protein were also analyzed in all tumor samples. Normal sized p53 mRNA and protein were present in all the tumor samples; however, their levels were 1.5- to 4-fold higher compared to the control suggesting deregulated p53 pathway in these tumors. No correlation was found between LOH status and the levels of p53 mRNA and protein. In all high-grade glioblastomas majority of the p53 protein existed as Ser 392 phosphorylated form as compared to low-grade gliomas. In addition, the percentage of Ser 392 phosphorylated form of p53 protein was lower in meningiomas and other brain tumor types irrespective of tumor grade. These results suggest involvement of Ser 392 phosphorylated form of p53 protein during the later stages of glioma development. These results also indicate that deregulation of p53 gene could occur at various steps in p53 pathway and suggest an overall deregulation of p53 gene in most brain tumor types.

p16INK4Aand p14ARFTumor Suppressor Pathways Are Deregulated in Malignant Rhabdoid Tumors

“…In a study involving CNS embryonal tumors, 2/3 AT/RT cases showed staining for p53 (49). No definitive correlation exists between p53 expression by immunohistochemistry and TP53 mutations in either CNS or non-CNS malignancies (50–54). There has been no systematic study of p53 immunohistochemistry and its relation to the mutational status in MRT.…”

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).…”

“…The levels of protein bands were estimated by measuring the band intensities using Bio-Rad (Bio-Rad, Australia) quantity 1 software for all the samples individually, and these values were normalized to the corresponding control 48 kDa -tubulin bands from the same samples [27,28]. The levels of p53 protein in WI38 cell line were taken as 1.0 and the levels in untreated controls samples were calculated based on their intensities and reported as level of increase [13,14]. The protein levels in the treated samples were calculated for each tumor tissue based on the corresponding untreated control and reported as level of decrease in the treated samples [13,14].…”

“…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.…”

Biomolecular characterization of human glioblastoma cells in primary cultures: Differentiating and antiangiogenic effects of natural and synthetic PPARγ agonists

“…Inhibition of apoptosis may also contribute to drug resistance since chemotherapeutic agents mostly act by inducing apoptosis. The finding that brain tumors either deficient in the p53 tumor suppressor gene or over‐expressing the antiapoptotic protein Bcl‐2 escape apoptosis and are resistant to radiotherapy and chemotherapy (Rohini et al, 2006; Stegh et al, 2007) indicates that tumor‐specific genetic lesions confer a survival advantage to tumor cells. Malignant progression of gliomas involves accumulation of genetic alterations inactivating p53, p16, RB, and PTEN tumor suppressor genes and/or activating oncogenes including the epidermal growth factor receptor (EGFR), CDK4, CDK6, and MDM2 genes (Schiffer, 1998; Ushio et al, 2003).…”