Oncogenic Intra-p53 Family Member Interactions in Human Cancers

Ferraiuolo, Maria; Agostino, Silvia Di; Blandino, Giovanni; Strano, Sabrina

doi:10.3389/fonc.2016.00077

Cited by 66 publications

(46 citation statements)

References 181 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the contrary, the over-expression of p73 gene was observed in several types of neoplasms, suggesting the oncogenic role of p73 gene in cancer development and progression [5]. The findings of either suppressor or oncogenic role of TP73 protein in carcinogenesis may be associated with different functions of several isoforms of the TP73 protein [4][5][6]. p73a mRNA variant encodes the longest protein isoform (69.6 kDa, 636aa) characterized by the occurrence of three domains: transactivation (TA), DNA-binding and proline-rich ones.…”

mentioning

confidence: 98%

Decreased expression of p73 in colorectal cancer

Kotulak

Wrońska

Godlewski

et al. 2016

Folia Histochem Cytobiol.

View full text Add to dashboard Cite

Introduction. The colorectal cancer (CRC) is one of the most frequent cancer in Poland and worldwide. This disease is characterized by distinct genetic alterations. p73 belongs to the p53 gene family; however, its role in the pathogenesis of CRC has not been completely understood. p73 gene encodes several mRNA variants and protein isoforms with its longest and fully functional p73a (mRNA) and TAp73a (protein) isoform. The aim of the study was to investigate p73 gene expression at the mRNA (p73a) and protein (TAp73a) levels in CRC. Material and methods. Small sections of the CRC tumor tissue and macroscopically unchanged colon mucosa and submucosa from the dissection margin were collected from 23 patients diagnosed with CRC. p73 mRNA levels were measured by Real-time PCR (QPCR) method and the expression level of TAp73a protein was assessed by Western blotting (WB) and immunohistochemical (IHC) staining. Results. We found a 37% decrease in the level of p73a mRNA in neoplastically changed (tumor) compared with unchanged normal colon tissue from the surgical margin (p = 0.041). No correlations were found between mRNA levels in cancer tissue and clinical-pathological parameters. The semi-quantification of TAp73a protein revealed lower and higher TAp73a protein contents in 11/23 and 12/23 of tumor samples, respectively, when compared with the median value of TAp73a protein in normal colon tissue (p = 0.61). The level of TAp73a protein level was 5 times lower in poorly differentiated cancer cells (G3) in comparison to moderately differentiated ones (G2; p = 0.02). No statistically significant correlations were observed between the level of the TAp73a protein and clinical-pathological patients' characteristics. The IHC analysis of TAp73a protein presence in CRC samples showed decreased immunoreactivity when compared with matched sections of the unchanged colon wall in 4/9 patients, similar intensity of the IHC reaction in 4/9 patients and increased immunoreactivity in 1/9 patients. The TAp73a protein was localized mainly in the cytoplasm of the cancer cells. No statistically significant correlations between IHC results and clinical-pathological features of the patients were found. Conclusions. The obtained results suggest that the p73 gene may play a role as a tumor suppressor in the CRC progression.

show abstract

mentioning

confidence: 98%

Decreased expression of p73 in colorectal cancer

Kotulak

Wrońska

Godlewski

et al. 2016

Folia Histochem Cytobiol.

View full text Add to dashboard Cite

show abstract

“…Its development and metastasis are governed by complex processes with multiple factors. Activation of cancer genes, deactivation of cancer suppressor genes, and over-expression of protein, among others, are important factors associated with the onset and progression of cancer (Xu et al, 2015a;Ferraiuolo et al, 2016). The p53 gene, which is located on 17P13.1 of the human chromosome, is 16-20 kb in length, and its mRNA, which is 2.5 kb, encodes a 393-amino-acid long protein.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance and expression of PUMA, MCL-1, and p53 in human renal cell carcinoma and para-carcinoma tissues

Xia

Cui²,

Su³

et al. 2017

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. We investigated the expression level of p53 upregulated modulator of apoptosis (PUMA), myeloid cell leukemia-I (MCL-1), and p53 in renal cell carcinoma (RCC) and para-carcinoma tissues, as well as their clinical significance. The expression levels of PUMA, MCL-1, and p53 in RCC and para-carcinoma tissues were measured using immunohistochemical and quantitative real-time PCR methods. Correlations between protein expression and pathological characteristics were analyzed. Renal clear cell carcinoma showed elevated MCL-1 and p53 protein expression (P > 0.05) and reduced PUMA expression as compared to that in para-carcinoma tissues. Spearman ranking correlation analysis showed that expression of PUMA, MCL-1, and p53 in was negatively correlated with RCC (r = -0.504, P = 0.001; r = -0.413, P = 0.008). We also observed significant correlation between 2 H.B. Xia et al. Genetics and Molecular Research 16 (3): gmr16039278MCL-1 expression and tumor differentiation (P < 0.05), where MCL-1 expression was significantly higher in well-differentiated adenocarcinoma as compared to that in medium or lowly differentiated adenocarcinoma. In addition, p53 expression was highly correlated with TNM staging (P < 0.05). Single factor analysis on COX's proportional hazard model indicated that postoperative survival rate and prognosis of renal clear cell carcinoma was highly correlated with TNM staging (P < 0.05). Quantitative real-time PCR analysis indicated higher expression of PUMA, MCL-1, and p53 in cancer tissues as compared to that in para-carcinoma tissues (P < 0.05).The expression of PUMA, MCL-1, and p53 can reflect the biological behavior of renal cell carcinoma, and can be used to indicate tumor invasion, progression, and prognosis.

show abstract

“…The other two members of the p53 family, p73 and p63 transcriptional factors, have 22-29% of homology in the transactivation domain (TAD), 63% in the DNA binding domain (DBD), and 42% in the oligomerization domain (OD) of p53 [19]. Both p73 and p63 can promote p53-independent DNA damage response (DDR), growth arrest, and apoptosis [20]. Human tumor-derived p53 mutants are observed to bind diverse p73 and p63 isoforms interfering with their transcriptional activity and inhibiting apoptosis induction and increasing chemoresistance mechanisms ( Figure 1) [20].…”

Section: Mutant P53 Gain-of-functionmentioning

confidence: 99%

The Impact of Mutant p53 in the Non-Coding RNA World

Agostino

2020

Biomolecules

Self Cite

View full text Add to dashboard Cite

Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.Biomolecules 2020, 10, 472 2 of 15 heterotetrameric mut-p53/wt-p53 complex can inhibit the function of the remaining wt-p53 in tumor suppression [8,9]. Most of the missense mutations occur in the p53 DNA-binding region and can be classified as either contact mutations (as p53R248 and p53R273 interfere directly with DNA binding) or conformational mutations (as p53R175 induces local or global conformational distortions) [5,9].Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered. mut-p53 GOF has been demonstrated by numerous cell-based experiments such as by ectopic expression of mut-p53 proteins in p53-null human tumor cells or knockdown of endogenous mut-p53 in cells containing only one allele of mutant p53, as well as in mutant p53 knock-in mouse models [5,[8][9][10]. Genome sequencencing has highlighted that more than 91% of TP53-mutant cancers exhibit loss of the second allele (LOH) by mutation or DNA deletion [11].Many mut-p53 GOF activities have been identified as tumor cell proliferation, survival, migration and invasion, enhancing chemoresistance, disrupting proper tissue architecture, inducing cancer metabolism (Warburg effect and lipid metabolism), and increasing genomic instability and mitochondrial dysfunction [5,[10][11][12][13][14][15] (Figure 1).

show abstract

Oncogenic Intra-p53 Family Member Interactions in Human Cancers

Cited by 66 publications

References 181 publications

Decreased expression of p73 in colorectal cancer

Decreased expression of p73 in colorectal cancer

Clinical significance and expression of PUMA, MCL-1, and p53 in human renal cell carcinoma and para-carcinoma tissues

The Impact of Mutant p53 in the Non-Coding RNA World

Contact Info

Product

Resources

About