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Gene Review

TP63  -  tumor protein p63

Homo sapiens

Synonyms: AIS, B(p51A), B(p51B), CUSP, Chronic ulcerative stomatitis protein, ...
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Disease relevance of TP73L


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


Chemical compound and disease context of TP73L


Biological context of TP73L


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


  1. P73 expression in basal layers of head and neck squamous epithelium: a role in differentiation and carcinogenesis in concert with p53 and p63? Faridoni-Laurens, L., Bosq, J., Janot, F., Vayssade, M., Le Bihan, M.L., Kaghad, M., Caput, D., Bénard, J., Ahomadegbe, J.C. Oncogene (2001) [Pubmed]
  2. The transactivating isoforms of p63 are overexpressed in high-grade follicular lymphomas independent of the occurrence of p63 gene amplification. Pruneri, G., Fabris, S., Dell'Orto, P., Biasi, M.O., Valentini, S., Del Curto, B., Laszlo, D., Cattaneo, L., Fasani, R., Rossini, L., Manzotti, M., Bertolini, F., Martinelli, G., Neri, A., Viale, G. J. Pathol. (2005) [Pubmed]
  3. Loss of p63 and cytokeratin 5/6 expression is associated with more aggressive tumors in endometrial carcinoma patients. Stefansson, I.M., Salvesen, H.B., Akslen, L.A. Int. J. Cancer (2006) [Pubmed]
  4. Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Natt, E., Kida, K., Odievre, M., Di Rocco, M., Scherer, G. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  5. Repeated long separations from pups produce depression-like behavior in rat mothers. Boccia, M.L., Razzoli, M., Prasad Vadlamudi, S., Trumbull, W., Caleffie, C., Pedersen, C.A. Psychoneuroendocrinology (2007) [Pubmed]
  6. The cusp of evolution and development: a model of cichlid tooth shape diversity. Streelman, J.T., Webb, J.F., Albertson, R.C., Kocher, T.D. Evol. Dev. (2003) [Pubmed]
  7. Lateralization of verbal memory and unilateral hippocampal sclerosis: evidence of task-specific effects. Saling, M.M., Berkovic, S.F., O'Shea, M.F., Kalnins, R.M., Darby, D.G., Bladin, P.F. Journal of clinical and experimental neuropsychology : official journal of the International Neuropsychological Society. (1993) [Pubmed]
  8. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Celli, J., Duijf, P., Hamel, B.C., Bamshad, M., Kramer, B., Smits, A.P., Newbury-Ecob, R., Hennekam, R.C., Van Buggenhout, G., van Haeringen, A., Woods, C.G., van Essen, A.J., de Waal, R., Vriend, G., Haber, D.A., Yang, A., McKeon, F., Brunner, H.G., van Bokhoven, H. Cell (1999) [Pubmed]
  9. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Osada, M., Ohba, M., Kawahara, C., Ishioka, C., Kanamaru, R., Katoh, I., Ikawa, Y., Nimura, Y., Nakagawara, A., Obinata, M., Ikawa, S. Nat. Med. (1998) [Pubmed]
  10. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Truong, A.B., Kretz, M., Ridky, T.W., Kimmel, R., Khavari, P.A. Genes Dev. (2006) [Pubmed]
  11. P73 functionally replaces p53 in Adriamycin-treated, p53-deficient breast cancer cells. Vayssade, M., Haddada, H., Faridoni-Laurens, L., Tourpin, S., Valent, A., Bénard, J., Ahomadegbe, J.C. Int. J. Cancer (2005) [Pubmed]
  12. Expression of p63 in primary cutaneous adnexal neoplasms and adenocarcinoma metastatic to the skin. Ivan, D., Hafeez Diwan, A., Prieto, V.G. Mod. Pathol. (2005) [Pubmed]
  13. p63 Immunohistochemistry in the distinction of adenoid cystic carcinoma from basaloid squamous cell carcinoma. Emanuel, P., Wang, B., Wu, M., Burstein, D.E. Mod. Pathol. (2005) [Pubmed]
  14. P63 is expressed in basal and myoepithelial cells of human normal and tumor salivary gland tissues. Bilal, H., Handra-Luca, A., Bertrand, J.C., Fouret, P.J. J. Histochem. Cytochem. (2003) [Pubmed]
  15. Expression of the GLUT1 glucose transporter, p63 and p53 in thyroid carcinomas. Kim, Y.W., Do, I.G., Park, Y.K. Pathol. Res. Pract. (2006) [Pubmed]
  16. The emerging p53 gene family. Kaelin, W.G. J. Natl. Cancer Inst. (1999) [Pubmed]
  17. TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria. Gressner, O., Schilling, T., Lorenz, K., Schulze Schleithoff, E., Koch, A., Schulze-Bergkamen, H., Maria Lena, A., Candi, E., Terrinoni, A., Valeria Catani, M., Oren, M., Melino, G., Krammer, P.H., Stremmel, W., Müller, M. EMBO J. (2005) [Pubmed]
  18. DNA-binding and transactivation activities are essential for TAp63 protein degradation. Ying, H., Chang, D.L., Zheng, H., McKeon, F., Xiao, Z.X. Mol. Cell. Biol. (2005) [Pubmed]
  19. Mutational analysis of the p63/p73L/p51/p40/CUSP/KET gene in human cancer cell lines using intronic primers. Hagiwara, K., McMenamin, M.G., Miura, K., Harris, C.C. Cancer Res. (1999) [Pubmed]
  20. p51/p63 Controls subunit alpha3 of the major epidermis integrin anchoring the stem cells to the niche. Kurata, S., Okuyama, T., Osada, M., Watanabe, T., Tomimori, Y., Sato, S., Iwai, A., Tsuji, T., Ikawa, Y., Katoh, I. J. Biol. Chem. (2004) [Pubmed]
  21. Spatial and isoform specific p63 expression in the male human urogenital tract. Saito, K., Kawakami, S., Okada, Y., Takazawa, R., Koga, F., Kageyama, Y., Kihara, K. J. Urol. (2006) [Pubmed]
  22. Gap junction protein connexin 43 serves as a negative marker for a stem cell-containing population of human limbal epithelial cells. Chen, Z., Evans, W.H., Pflugfelder, S.C., Li, D.Q. Stem Cells (2006) [Pubmed]
  23. Endogenous p63 acts as a survival factor for tumour cells of SCCHN origin. Thurfjell, N., Coates, P.J., Vojtesek, B., Benham-Motlagh, P., Eisold, M., Nylander, K. Int. J. Mol. Med. (2005) [Pubmed]
  24. p63 expression in benign and malignant breast lesions. Stefanou, D., Batistatou, A., Nonni, A., Arkoumani, E., Agnantis, N.J. Histol. Histopathol. (2004) [Pubmed]
  25. Inhibition of epidermal growth factor receptor signaling decreases p63 expression in head and neck squamous carcinoma cells. Matheny, K.E., Barbieri, C.E., Sniezek, J.C., Arteaga, C.L., Pietenpol, J.A. Laryngoscope (2003) [Pubmed]
  26. High thermostability and lack of cooperative DNA binding distinguish the p63 core domain from the homologous tumor suppressor p53. Klein, C., Georges, G., Künkele, K.P., Huber, R., Engh, R.A., Hansen, S. J. Biol. Chem. (2001) [Pubmed]
  27. Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck. Thurfjell, N., Coates, P.J., Uusitalo, T., Mahani, D., Dabelsteen, E., Dahlqvist, A., Sjöström, B., Roos, G., Nylander, K. Int. J. Oncol. (2004) [Pubmed]
  28. P63 expression in papillary and anaplastic carcinomas of the thyroid gland: lack of an oncogenetic role in tumorigenesis and progression. Preto, A., Reis-Filho, J.S., Ricardo, S., Soares, P. Pathol. Res. Pract. (2002) [Pubmed]
  29. The p53-homologue p63 may promote thyroid cancer progression. Malaguarnera, R., Mandarino, A., Mazzon, E., Vella, V., Gangemi, P., Vancheri, C., Vigneri, P., Aloisi, A., Vigneri, R., Frasca, F. Endocr. Relat. Cancer (2005) [Pubmed]
  30. The human MDM2 oncoprotein increases the transcriptional activity and the protein level of the p53 homolog p63. Calabrò, V., Mansueto, G., Parisi, T., Vivo, M., Calogero, R.A., La Mantia, G. J. Biol. Chem. (2002) [Pubmed]
  31. GPX2, a direct target of p63, inhibits oxidative stress-induced apoptosis in a p53-dependent manner. Yan, W., Chen, X. J. Biol. Chem. (2006) [Pubmed]
  32. p300 regulates p63 transcriptional activity. MacPartlin, M., Zeng, S., Lee, H., Stauffer, D., Jin, Y., Thayer, M., Lu, H. J. Biol. Chem. (2005) [Pubmed]
  33. TAp63gamma can substitute for p53 in inducing expression of the maspin tumor suppressor. Spiesbach, K., Tannapfel, A., Mössner, J., Engeland, K. Int. J. Cancer (2005) [Pubmed]
  34. P63 and EGFR as prognostic predictors in stage IIB radiation-treated cervical squamous cell carcinoma. Cho, N.H., Kim, Y.B., Park, T.K., Kim, G.E., Park, K., Song, K.J. Gynecol. Oncol. (2003) [Pubmed]
  35. A novel response element confers p63- and p73-specific activation of the WNT4 promoter. Osada, M., Park, H.L., Nagakawa, Y., Begum, S., Yamashita, K., Wu, G., Kim, M.S., Trink, B., Sidransky, D. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  36. CUSP/p63 expression in rat and human tissues. Dellavalle, R.P., Egbert, T.B., Marchbank, A., Su, L.J., Lee, L.A., Walsh, P. J. Dermatol. Sci. (2001) [Pubmed]
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