Disease relevance of TP73L

• Immunostaining for p63, another p53-related protein previously described as being involved in HNSE morphogenesis and overexpressed in head and neck squamous cell carcinomas (HNSCC), was found to be similar to p73 labelling in carcinomas, but spread to the more differentiated layers in normal epithelium [1].
• We analysed p63 alterations by immunohistochemistry, quantitative real-time RT-PCR and FISH in a series of 45 follicular lymphomas (FL) [2].
• Absence of p63 expression (70%) was significantly associated with nonendometrioid carcinomas, high histologic grade (FIGO), higher mitotic count and tumor cell proliferation by Ki-67, microsatellite instability (MSI) and loss of hMSH6 expression [3].
• In complex hyperplasia, p63 expression was also increased, whereas CK5/6 was positive in areas with squamous differentiation only [3].
• In endometrial carcinoma, there is very limited information about the expression pattern of p63 or CK5/6 and no prognostic information [3].

Psychiatry related information on TP73L

• Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels [4].
• Long maternal (LMS) versus brief maternal (BMS) daily separations of rat pups from their mothers have contrasting effects on their adult stress responses and maternal behavior by, respectively, decreasing and increasing licking received from their mothers [5].
• We hypothesized that LMS decreases pup-licking in mothers by inducing learned helplessness, creating a depression-like state [5].
• Tooth shape is a hallmark of repeated evolutionary radiations among cichlid fishes from East Africa. Cusp shape and number vary both within populations and among closely related species with different feeding behaviors and ecologies [6].
• This study retrospectively investigated the effect of left (LHS) versus right (RHS) hippocampal sclerosis on verbal memory, measured by means of the Paired Associate Learning and Logical Memory subtests of the Wechsler Memory Scale (WMS) administered as part of a routine preoperative assessment [7].

High impact information on TP73L

• Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome [8].
• Transactivation studies with these mutant p63 isotypes provide a molecular explanation for the dominant character of p63 mutations in EEC syndrome [8].
• Eight mutations result in amino acid substitutions that are predicted to abolish the DNA binding capacity of p63 [8].
• In contrast with the ubiquitous expression of p53, expression of p51 mRNA was found in a limited number of tissues, including skeletal muscle, placenta, mammary gland, prostate, trachea, thymus, salivary gland, uterus, heart and lung [9].
• Contrasting roles for p63 in either the initial commitment to the stratified epithelial cell fate or in stem cell-based self-renewal have been proposed [10].

Chemical compound and disease context of TP73L

• Here, we compared for the first time to our knowledge p73 and p63 activation in various breast cancer (BC) cell lines after Adriamycin (ADR) treatment, an agent considered as mandatory in breast cancer chemotherapy [11].
• Immunohistochemical analysis for p63 was performed on formalin-fixed, paraffin-embedded archival tissue from 20 benign adnexal tumors, 10 malignant adnexal tumors and 14 adenocarcinomas metastatic to the skin [12].
• Archival, routinely processed slides were subjected to citrate-based antigen retrieval, exposure to anti-p63 monoclonal 4A4, and developed with a streptavidin-biotin kit and diaminobenzidine as chromogen. p63 was detected in 100% of the adenoid cystic carcinomas (n=14) and 100% of basaloid squamous cell carcinomas (n=16) [13].
• In all tumor types differentiated towards luminal and myoepithelial lineages (pleomorphic adenomas, basal cell adenomas, adenoid cystic carcinomas, and epithelial-myoepithelial carcinomas), p63 was expressed in myoepithelial cells, whereas luminal cells were always negative [14].
• Expression of the GLUT1 glucose transporter, p63 and p53 in thyroid carcinomas [15].

Biological context of TP73L

• Additional studies are required to determine the role, if any, that p73 and p51 play in cell growth control and carcinogenesis [16].
• TP63, an important epithelial developmental gene, has significant homology to p53 [17].
• In addition, the N-terminal transactivation domain of p63 is indispensable for its protein degradation [18].
• Accumulating evidence indicates that TAp63 plays an important role in regulation of cell proliferation, differentiation, and apoptosis, whereas transactivation-inert deltaNp63 functions to inhibit p63 and other p53 family members [18].
• In this study, we show that mutant p63 proteins with a single amino acid substitution found in EEC syndrome are DNA binding deficient, transactivation inert, and highly stable [18].

Anatomical context of TP73L

• We conclude that mutations in the p63 gene are rare in human cell lines [19].
• The high level alpha(3) production in human keratinocyte stem cells diminished upon elimination of p51/p63 by small interfering RNA or by Ca(2+)-induced differentiation [20].
• When activated by genotoxic stress or overexpressed ectopically in non-adherent cells, p51/p63 transduced a phenotype to attach to extracellular matrices, which was accompanied by expression of ITGA3 [20].
• Quantitative RT-PCR analysis showed that all cases but one had TA-p63 mRNA levels higher than non-neoplastic lymphocytes, and that TA-p63 mRNA expression correlated significantly (r = 0.9194, p < 0.0001) with the prevalence of p63 immunoreactivity [2].
• RESULTS: Basal cells in the stratified epithelium of the urinary and reproductive tracts, including the urothelium, prostate, seminal vesicle, ductus deferens and ductus epididymidis, showed intense nuclear immunostaining for p63 [21].

Associations of TP73L with chemical compounds

• We describe here identification of ITGA3 encoding integrin alpha(3) as a target of its trans-activating function, proposing that p51/p63 allows epidermal stem cells to express laminin receptor alpha(3)beta(1) for anchorage to the basement membrane [20].
• The Cx43(dim) cells were found to contain higher percentages of slow-cycling bromodeoxyuridine (BrdU)-label retaining cells and the cells that were positive for stem cell-associated markers p63, ABCG2, and integrin beta1 and negative for differentiation markers K3 and involucrin [22].
• We also demonstrate that inhibition of endogenous p63 expression sensitises cells to the effects of ionizing radiation and cisplatin, common treatments for SCCHN patients [23].
• In all benign lesions, p63 immunoreactivity was noted in the myoepithelial cell layer surrounding the luminal epithelial cells [24].
• RESULTS: In SCC-012 cells there was a dose-dependent decrease in p63 protein and messenger RNA levels over the course of ZD1839 treatment [25].

Physical interactions of TP73L

• In contrast to p53, the free p63 core domain did not show specific binding to p53 DNA consensus sites [26].

Regulatory relationships of TP73L

• 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 [27].
• However, alternative mechanisms to overcome p53 tumor suppressing properties in WDTCs and anaplastic carcinomas (ACs) have not been clarified to date. p63, a p53-homologue, has been recently characterized [28].
• The p53-homologue p63 may promote thyroid cancer progression [29].
• These data indicate that p63 can be activated by HDM2 under conditions in which p53 is inhibited [30].
• Accordingly, a unique responsive element was found in the promoter of the GPX2 gene that can be activated and bound by p63 but not p53 [31].

Other interactions of TP73L

• Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DeltaNp63 [17].
• We demonstrate that TAp63 protein expression is tightly controlled by its specific DNA-binding and transactivation activities and that p63 is degraded in a proteasome-dependent, MDM2-independent pathway [18].
• These results suggest that p300 regulates p63-dependent transcription of p21 [32].
• Interestingly, the majority of tumors expressing only a mutated and inactive p53 protein nonetheless stain positive for maspin, whereas these tumors were positive for p63 protein expression [33].
• p63 and cytokeratin (CK) 5/6 are markers of basal and squamous differentiation in several normal epithelia and human tumors and are also suggested to be markers of progenitor or stem cells in certain stratified epithelia [3].

Analytical, diagnostic and therapeutic context of TP73L

• 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 [2].
• The clinicopathologic features, patterns of treatment failure, and survival data were compared with the expressions of p63 and EGFR, which were determined by immunohistochemistry and with apoptosis by TUNEL on tissue-arrayed slides [34].
• In this study, we demonstrated differential target gene activation by specific p53, p63, and p73 induction in Saos2 cells by oligonucleotide microarray expression analysis [35].
• Immunofluorescence reveals p63 expression in skin, oral epithelium, tongue, kidney, and trachea, but not in liver, large intestine, testis, skeletal muscle, or heart [36].
• We have examined p63 expression by Northern analysis of RNA from multiple human tissues and by indirect immunofluorescence of rat tissue with CUS patient sera [36].

References