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Trp63  -  transformation related protein 63

Mus musculus

Synonyms: AI462811, KET protein, Ket, P51/P63, P63, ...
 
 
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Disease relevance of Trp63

  • In contrast, p63 protein is not detected in human prostate adenocarcinomas [1].
  • Furthermore, p63+/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas [2].
  • P63 was also essential for uterine squamous metaplasia induced by DES-exposure [3].
  • Mice lacking the p53/p63 target gene Perp are resistant to papilloma development [4].
  • Defects in the first pathway explain imperforate anus, vaginal septum, genital hypoplasia, and micropenis reported in humans with p63 mutations [5].
 

Psychiatry related information on Trp63

  • Finally, to better evaluate the potential role of p63 in human development of DES-induced cervical/vaginal adenosis, we describe the ontogeny of p63 in human female fetuses [6].
 

High impact information on Trp63

  • Perp is a p63-regulated gene essential for epithelial integrity [7].
  • We show here that Perp, a tetraspan membrane protein originally identified as an apoptosis-associated target of the p53 tumor suppressor, is the first direct target of p63 clearly involved in mediating this developmental program in vivo [7].
  • During embryogenesis, Perp is expressed in an epithelial pattern, and its expression depends on p63 [7].
  • p63 is a p53 homologue required for limb and epidermal morphogenesis [8].
  • Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm [9].
 

Biological context of Trp63

  • These findings demonstrate that Perp is a key effector in the p63 developmental program, playing an essential role in an adhesion subprogram central to epithelial integrity and homeostasis [7].
  • Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53 [10].
  • Overexpression of TAp63 causes neuronal apoptosis in the presence of NGF, while cultured p63-/- neurons are resistant to apoptosis following NGF withdrawal [11].
  • The epidermal phenotype was reminiscent of defects seen in p63(-/-) mice [12].
  • Consistent with this, reduced p63 expression was observed in transgenic offspring expressing either RAR mutant, suggesting that down-regulation of p63 might underlie the effects of these receptors on epidermal development [12].
 

Anatomical context of Trp63

  • Another novel finding reported in this study is the fact that p63(-/-) mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium [13].
  • These results indicate that p63 is required for prostate development and support the hypothesis that basal cells represent and/or include prostate stem cells [1].
  • It has been previously shown that p63 is expressed in normal urothelium [13].
  • Mouse embryo fibroblasts derived from deltaEF1-deficient mice exhibit unbalanced expression of DeltaNp63, TAp73 and DeltaNp73 but not of TAp63 and p53 [14].
  • Interestingly, TAp63 variants, which include the conserved transactivation domain TA at their amino-terminus, were also expressed in wound keratinocytes as well as at the edge of the injured subcutaneous muscle panniculus carnosus [15].
 

Associations of Trp63 with chemical compounds

  • Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin) [16].
  • Prostatic tissue that developed in p63(-/-) UGS grafts contained neuroendocrine and luminal cells, but basal cells were absent [17].
  • Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis [3].
  • However, regressed p63(-/-) prostate did regenerate in response to androgen administration, indicating that basal cells were not essential for prostatic regeneration [17].
  • In the human fetus at the susceptible stage for DES-induced cervical/vaginal adenosis, most cervical/vaginal epithelial cells were columnar and negative for p63 [6].
 

Physical interactions of Trp63

  • Additional demonstration with known p53 response elements suggested that DNA-binding profiles of p51A and p73L were very similar but were distinct from that of p53 [18].
 

Co-localisations of Trp63

  • Moreover, p63 expression in tooth seems not to be fully colocalized with nuclear Ki67 expression [19].
 

Regulatory relationships of Trp63

 

Other interactions of Trp63

 

Analytical, diagnostic and therapeutic context of Trp63

References

  1. p63 is a prostate basal cell marker and is required for prostate development. Signoretti, S., Waltregny, D., Dilks, J., Isaac, B., Lin, D., Garraway, L., Yang, A., Montironi, R., McKeon, F., Loda, M. Am. J. Pathol. (2000) [Pubmed]
  2. p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors. Keyes, W.M., Vogel, H., Koster, M.I., Guo, X., Qi, Y., Petherbridge, K.M., Roop, D.R., Bradley, A., Mills, A.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis. Kurita, T., Mills, A.A., Cunha, G.R. Development (2004) [Pubmed]
  4. Mice lacking the p53/p63 target gene Perp are resistant to papilloma development. Marques, M.R., Horner, J.S., Ihrie, R.A., Bronson, R.T., Attardi, L.D. Cancer Res. (2005) [Pubmed]
  5. p63 Coordinates anogenital modeling and epithelial cell differentiation in the developing female urogenital tract. Ince, T.A., Cviko, A.P., Quade, B.J., Yang, A., McKeon, F.D., Mutter, G.L., Crum, C.P. Am. J. Pathol. (2002) [Pubmed]
  6. Differential expression of p63 isoforms in female reproductive organs. Kurita, T., Cunha, G.R., Robboy, S.J., Mills, A.A., Medina, R.T. Mech. Dev. (2005) [Pubmed]
  7. Perp is a p63-regulated gene essential for epithelial integrity. Ihrie, R.A., Marques, M.R., Nguyen, B.T., Horner, J.S., Papazoglu, C., Bronson, R.T., Mills, A.A., Attardi, L.D. Cell (2005) [Pubmed]
  8. p63 is a p53 homologue required for limb and epidermal morphogenesis. Mills, A.A., Zheng, B., Wang, X.J., Vogel, H., Roop, D.R., Bradley, A. Nature (1999) [Pubmed]
  9. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R.T., Tabin, C., Sharpe, A., Caput, D., Crum, C., McKeon, F. Nature (1999) [Pubmed]
  10. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M.D., Dötsch, V., Andrews, N.C., Caput, D., McKeon, F. Mol. Cell (1998) [Pubmed]
  11. p63 is an essential proapoptotic protein during neural development. Jacobs, W.B., Govoni, G., Ho, D., Atwal, J.K., Barnabe-Heider, F., Keyes, W.M., Mills, A.A., Miller, F.D., Kaplan, D.R. Neuron (2005) [Pubmed]
  12. Dominant-negative retinoic acid receptors elicit epidermal defects through a non-canonical pathway. Chen, C.F., Lohnes, D. J. Biol. Chem. (2005) [Pubmed]
  13. Loss of p63 expression is associated with tumor progression in bladder cancer. Urist, M.J., Di Como, C.J., Lu, M.L., Charytonowicz, E., Verbel, D., Crum, C.P., Ince, T.A., McKeon, F.D., Cordon-Cardo, C. Am. J. Pathol. (2002) [Pubmed]
  14. deltaEF1 repressor controls selectively p53 family members during differentiation. Fontemaggi, G., Gurtner, A., Damalas, A., Costanzo, A., Higashi, Y., Sacchi, A., Strano, S., Piaggio, G., Blandino, G. Oncogene (2005) [Pubmed]
  15. Expression of different p63 variants in healing skin wounds suggests a role of p63 in reepithelialization and muscle repair. Bamberger, C., Hafner, A., Schmale, H., Werner, S. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. (2005) [Pubmed]
  16. Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice. Candi, E., Rufini, A., Terrinoni, A., Dinsdale, D., Ranalli, M., Paradisi, A., De Laurenzi, V., Spagnoli, L.G., Catani, M.V., Ramadan, S., Knight, R.A., Melino, G. Cell Death Differ. (2006) [Pubmed]
  17. Role of p63 and basal cells in the prostate. Kurita, T., Medina, R.T., Mills, A.A., Cunha, G.R. Development (2004) [Pubmed]
  18. Identification of a novel retrovirus long terminal repeat (LTR) that is targeted by p51A (TAp63gamma) and selective dominant-negative activity of p73L (DeltaNp63alpha) toward p53-responsive promoter activities. Senoo, M., Matsumura, Y., Habu, S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  19. p63 protein is essential for the embryonic development of vibrissae and teeth. Rufini, A., Weil, M., McKeon, F., Barlattani, A., Melino, G., Candi, E. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  20. A role for chromosomal protein HMGN1 in corneal maturation. Birger, Y., Davis, J., Furusawa, T., Rand, E., Piatigorsky, J., Bustin, M. Differentiation (2006) [Pubmed]
  21. The oncogenic roles of p53 mutants in mouse models. Lozano, G. Curr. Opin. Genet. Dev. (2007) [Pubmed]
  22. Notch1-expressing cells are indispensable for prostatic branching morphogenesis during development and re-growth following castration and androgen replacement. Wang, X.D., Shou, J., Wong, P., French, D.M., Gao, W.Q. J. Biol. Chem. (2004) [Pubmed]
  23. p63 regulates commitment to the prostate cell lineage. Signoretti, S., Pires, M.M., Lindauer, M., Horner, J.W., Grisanzio, C., Dhar, S., Majumder, P., McKeon, F., Kantoff, P.W., Sellers, W.R., Loda, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  24. Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects. Lo Iacono, N., Mantero, S., Chiarelli, A., Garcia, E., Mills, A.A., Morasso, M.I., Costanzo, A., Levi, G., Guerrini, L., Merlo, G.R. Development (2008) [Pubmed]
  25. Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16. Augustin, M., Bamberger, C., Paul, D., Schmale, H. Mamm. Genome (1998) [Pubmed]
  26. Identification of potential biomarkers of genotoxicity and carcinogenicity in L5178Y mouse lymphoma cells by cDNA microarray analysis. Kim, J.Y., Kwon, J., Kim, J.E., Koh, W.S., Chung, M.K., Yoon, S., Song, C.W., Lee, M. Environ. Mol. Mutagen. (2005) [Pubmed]
  27. Differential recognition of response elements determines target gene specificity for p53 and p63. Osada, M., Park, H.L., Nagakawa, Y., Yamashita, K., Fomenkov, A., Kim, M.S., Wu, G., Nomoto, S., Trink, B., Sidransky, D. Mol. Cell. Biol. (2005) [Pubmed]
 
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