Disease relevance of TP73

• Therapeutic efficacy of E2F1 in pancreatic cancer correlates with TP73 induction [1].
• In some tumours, most notably leukaemias and lymphomas, expression of TP73 is reduced, suggesting a tumour suppressor role [2].
• Importantly, alterations to the proposed regulatory pathway for controlling TP73 isoform expression in colorectal cancer are associated with adverse clinico-pathological characteristics [2].
• Quantitative TP73 transcript analysis in hepatocellular carcinomas [3].
• Different expression of P14ARF defines two groups of breast carcinomas in terms of TP73 expression and TP53 mutational status [4].

Psychiatry related information on TP73

• TP73 is therefore of interest as a candidate gene for Alzheimer's disease (AD) susceptibility [5].

High impact information on TP73

• We propose that the disregulation of p73 contributes to tumorigenesis and that p53-related proteins operate in a network of developmental and cell cycle controls [6].
• A p53-related gene, p73, which encodes several proteins as a result of alternative splicing, can also induce apoptosis [7].
• Deregulated expression of DeltaNp73 can bestow oncogenic activity upon the TP73 gene by functionally inactivating the suppressor action of p53 and TAp73 [8].
• We report that the human TP73 gene generates an NH(2) terminally truncated isoform [8].
• Maximum synthesis of both proteins is reached by 12 h after mitogen addition when P95 synthesis represents approximately 4%, and P73 approximately 2%, of the total protein synthesis, compared with less than 0.5% for each protein in cells cultured without mitogen [9].

Chemical compound and disease context of TP73

• P73 functionally replaces p53 in Adriamycin-treated, p53-deficient breast cancer cells [10].
• These results suggested that the antitumor property of 5FU enhanced by pharmacokinetic modulation might have a lethal effect on rectal tumors with a loss of the p53-related apoptosis pathway [11].
• METHODS: Phosphorothioate oligonucleotides were used to target p53-related sequences in two p53-mutant/overexpressing endometrial cancer cell lines (KLE and RL95-2) and a normal fibroblast control [12].
• AIM: To investigate the signal pathway of honokiol-induced apoptosis on human colorectal carcinoma RKO cells and to evaluate whether p53 and p53-related genes were involved in honokiol-treated RKO cells [13].

Biological context of TP73

• In contrast to TP53, tumor-associated overexpression of TP73 in many different cancers, combined with virtual absence of inactivating mutations and lack of a cancer phenotype in the TP73 null mouse are inconsistent with a suppressor function but instead support an oncogenic function [14].
• These data show that oncogenes can signal to TP73 in vivo [15].
• Bisulfite genomic sequencing detected aberrant hypermethylation at the 5' region upstream and including the first exon of the TP73 gene in 17 of 44 (39%) oligodendroglial tumors, whereas normal brain tissues showed no methylation in the same region examined [16].
• The TP73 gene, located on chromosome 1p36.3, encodes a product that shares significant structural homology with the tumor suppressor TP53 [16].
• In conclusion, our results showed that inactivation of TP73 occurs at the transcriptional level and is associated with promotor hypermethylation [16].

Anatomical context of TP73

• The analysis of concomitant P14ARF and TP73 overexpression and clinicopathologic parameters of the tumors showed a statistically significant difference with respect to peritumoral vessel invasion (P = 0.01), lymph node metastasis (P = 0.03), negative ERBB2 expression (P = 0.005), and more advanced pathologic stages (P = 0.03) [4].
• RESULTS: Using a coding-neutral BanI polymorphism in TP73 exon 5 as an allelic marker, we found a pronounced allelic expression bias in one adult brain hippocampus, while 3 other brains (two adult; one fetal) showed approximately equal expression from both alleles [5].
• Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders [17].
• p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells [17].
• Establishment of a cell line with AML1-MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia [18].

Associations of TP73 with chemical compounds

• Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin [19].
• Mutation in p53 and de-regulation of p53-related gene expression in three human cell lines immortalized with 4-nitroquinoline 1-oxide or 60Co gamma rays [20].
• Such treatment also induced p73, a p53-related transcription factor regulated by c-Abl kinase, and enhanced the sensitivity to fludarabine (F-ara-A) of CLL cells lacking functional p53 [21].
• beta-Carotene exacerbates DNA oxidative damage and modifies p53-related pathways of cell proliferation and apoptosis in cultured cells exposed to tobacco smoke condensate [22].
• In terms of changes in expression of p53-related proteins, increase in expression of Bax and decrease in that of Bcl-2 were observed in TE-2 but not in TE-1, suggesting that the main mode of cell death induced by genistein in a cell line with wild type p53 differed from that with mutant p53 [23].

Physical interactions of TP73

• MDM2 and MDMX bind and stabilize the p53-related protein p73 [24].

Regulatory relationships of TP73

• As an alternative, TP73 may be inactivated through aberrant 5' CpG island methylation, a primary mechanism participating in the inactivation of tumor suppressor genes during tumorigenesis [25].
• The human p63 gene encodes a series of protein isoforms that differ in their N- and/or C-terminal sequences and possess widely varying activities in promoting or repressing p53-related functions and in regulating the proliferation and differentiation of epithelial cells [26].

Other interactions of TP73

• Despite strong homology, the roles of TP53 and TP73 in tumorigenesis seem to be fundamentally different [14].
• DFFB maps to 1p36, near the imprinted putative tumour suppressor gene TP73 [27].
• This aberration seems to occur early in the carcinogenesis process (it is already present in the low-grade forms), although in some instances (DAPK, THBS1, and TP73) it appears also associated with the genesis of anaplastic forms [28].
• Recent data provide evidence for interacting roles of ZEB1, p300, and a polymorphic 73 bp deletion in intron 1 of the human TP73 gene in this process [2].
• The genes PLA2G2A (1p35.1-36) and TP73 (1p36.3) were shown to lie outside this consistently lost region, suggesting that neither of them are targets for the 1p loss [29].

Analytical, diagnostic and therapeutic context of TP73

• The expression of TP73 was analyzed by quantitative RT-PCR, and loss of heterozygosity (LOH) was assessed by microsatellite study [30].
• The association of levels of TP53 mutation and TP73 expression with ET-743 sensitivity and cell cycle kinetics after treatment was also analyzed [31].
• We have searched for p53-related genes by using degenerate PCR, and have identified two cDNA fragments similar to but distinct from p53: one previously reported, p73, and the other new [32].
• However, immunohistochemistry consistently revealed that all the tumour cells express substantial amounts of the p53-related protein p63 [33].
• p63 is a p53-related gene mapping to 3q28 that codes for multiple mRNA transcripts with (TA-p63) or without (DeltaN-p63) transactivating effects on genes that promote cell differentiation and apoptosis [34].

References