P63

位於3號人類染色體的基因

p63,亦作TP63,全稱腫瘤蛋白p63(tumor protein p63)或惡性轉化相關蛋白63(transformation-related protein 63),在人體內由TP63基因編碼[6][7][8][9]。p63的發現是在p53基因發現後20年。p63與p53、p73同屬一個蛋白家族,三者結構與功能都較爲相似[10]。儘管p63的發現晚於p53,但進化生物學的證據表明p63是p53蛋白家族的起源,p53、p73都是由p63蛋白演化而成[11]

P63
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
别名TP63;, AIS, B(p51A), B(p51B), EEC3, KET, LMS, NBP, OFC8, RHS, SHFM4, TP53CP, TP53L, TP73L, p40, p51, p53CP, p63, p73H, p73L, tumor protein p63
外部IDOMIM603273 MGI1330810 HomoloGene31189 GeneCardsTP63
相關疾病
肺腺癌、​lymphoblastic leukemia、​肺癌、​ADULT綜合徵、​附肢-乳腺綜合徵、​AEC綜合徵、​split hand-foot malformation 2[1]
基因位置(人类
3號染色體
染色体3號染色體[2]
3號染色體
P63的基因位置
P63的基因位置
基因座3q28起始189,631,389 bp[2]
终止189,897,276 bp[2]
RNA表达模式




查阅更多表达数据
直系同源
物種人類小鼠
Entrez
Ensembl
UniProt
mRNA​序列
蛋白序列
基因位置​(UCSC)Chr 3: 189.63 – 189.9 MbChr 16: 25.5 – 25.71 Mb
PubMed​查找[4][5]
維基數據
檢視/編輯人類檢視/編輯小鼠

功能

p63是p53蛋白家族下的一種轉錄因子。p63-/-基因型的小鼠會出現無乳腺等發育依賴間充質-上皮相互作用的器官組織及無附肢等多種發育缺陷。p63蛋白的轉錄變體主要有兩種,TAp63和ΔNp63。已證明ΔNp63擁有多種功能,包括參與皮膚發育和成體幹細胞/祖細胞的功能調控[12]。相比之下,傳統的觀點認爲TAp63的功能幾乎只侷限於參與凋亡過程。不過,近期的研究還表明TAp63參與了卵母細胞完整性的維持[13]。另一些研究還表明TAp63參與了心臟發育[14]和早衰過程[15]

臨床意義

p63蛋白的突變可能會導致兔脣、腭裂等發育畸形[16]。p63蛋白的突變可導致以等裂兔脣爲典型特徵的EEC綜合徵英语ectrodactyly-ectodermal dysplasia-cleft syndrome(ectrodactyly-ectodermal dysplasia-cleft syndrom)[16]。此外,p63蛋白的突變也可能導致3型兔脣腭裂綜合徵英语cleft lip/palate syndrome 3(EEC3)、先天性缺指英语ectrodactyly(ectrodactyly,亦稱爲裂手-腳畸形4),以及以等裂兔脣爲典型特徵的AEC綜合徵英语Hay–Wells syndrome[16]。此外,ADULT綜合徵英语Acro–dermato–ungual–lacrimal–tooth syndrome(Acro–dermato–ungual–lacrimal–tooth syndrome)、附肢-乳腺綜合徵英语limb-mammary syndrome(limb-mammary syndrome)、RHS綜合徵英语Rap-Hodgkin syndrome(Rap-Hodgkin syndrome)以及也與p63蛋白功能的異常有關。目前認爲兔脣、腭裂是同時出現還是任出現一種取決於p63的不同突變[16]近期,研究人員提出使用iPS細胞分化替代缺陷型上皮細胞治療EEC綜合徵的方法[17]

診斷

p63的免疫組化法可以用於診斷扁平細胞癌和前列腺腺癌(最常見的一種前列腺癌)[18]。正常的前列腺腺體含有基底細胞,因而組織高表達p63,免疫染色深,而惡性轉化後的腺癌組織因缺少基底細胞,p63免疫染色呈現陰性結果[19]。p63亦可用於鑑別腺癌、小細胞癌中常見的分化程度低的癌變扁平細胞[20]

相互作用

p63可與HNRPAB英语HNRPAB蛋白發生相互作用[21]。同樣,p63可以通過與轉錄因子IRF6英语IRF6增強子結合激活其轉錄[16]

調節

研究表明p63的表達受miRNAmiR-203英语miR-203的調控[22][23]

參見

  • AMACR英语AMACR,另一種前列腺癌的腫瘤標誌物

参考文献

  1. ^ 與P63相關的疾病;在維基數據上查看/編輯參考. 
  2. ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000073282 - Ensembl, May 2017
  3. ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000022510 - Ensembl, May 2017
  4. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  6. ^ Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Molecular Cell. Sep 1998, 2 (3): 305–16. PMID 9774969. doi:10.1016/S1097-2765(00)80275-0. 
  7. ^ Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nature Medicine. Jul 1998, 4 (7): 839–43. PMID 9662378. doi:10.1038/nm0798-839. 
  8. ^ Zeng X, Zhu Y, Lu H. NBP is the p53 homolog p63. Carcinogenesis. Feb 2001, 22 (2): 215–9. PMID 11181441. doi:10.1093/carcin/22.2.215. 
  9. ^ Tan M, Bian J, Guan K, Sun Y. p53CP is p51/p63, the third member of the p53 gene family: partial purification and characterization. Carcinogenesis. Feb 2001, 22 (2): 295–300. PMID 11181451. doi:10.1093/carcin/22.2.295. 
  10. ^ Wu G, Nomoto S, Hoque MO, Dracheva T, Osada M, Lee CC, Dong SM, Guo Z, Benoit N, Cohen Y, Rechthand P, Califano J, Moon CS, Ratovitski E, Jen J, Sidransky D, Trink B. DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Research. May 2003, 63 (10): 2351–7. PMID 12750249. 
  11. ^ Skipper M. Dedicated protection for the female germline. Nature Reviews Molecular Cell Biology. January 2007, 8 (1): 4–5. doi:10.1038/nrm2091. 
  12. ^ Crum CP, McKeon FD. p63 in epithelial survival, germ cell surveillance, and neoplasia. Annual Review of Pathology. 2010, 5: 349–71. PMID 20078223. doi:10.1146/annurev-pathol-121808-102117. 
  13. ^ Deutsch GB, Zielonka EM, Coutandin D, Weber TA, Schäfer B, Hannewald J, Luh LM, Durst FG, Ibrahim M, Hoffmann J, Niesen FH, Sentürk A, Kunkel H, Brutschy B, Schleiff E, Knapp S, Acker-Palmer A, Grez M, McKeon F, Dötsch V. DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer. Cell. Feb 2011, 144 (4): 566–76. PMC 3087504 . PMID 21335238. doi:10.1016/j.cell.2011.01.013. 
  14. ^ Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, De Rosa L, Candi E, de la Forest Divonne S, Mikkola ML, van Bokhoven H, Missero C, Melino G, Pucéat M, Aberdam D. TAp63 is important for cardiac differentiation of embryonic stem cells and heart development. Stem Cells. Nov 2011, 29 (11): 1672–83 [2017-11-13]. PMID 21898690. doi:10.1002/stem.723. (原始内容存档于2014-08-08). 
  15. ^ Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER. TAp63 prevents premature aging by promoting adult stem cell maintenance. Cell Stem Cell. Jul 2009, 5 (1): 64–75. PMC 3418222 . PMID 19570515. doi:10.1016/j.stem.2009.04.003. 
  16. ^ 16.0 16.1 16.2 16.3 16.4 Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nature Reviews Genetics. Mar 2011, 12 (3): 167–78. PMC 3086810 . PMID 21331089. doi:10.1038/nrg2933. 
  17. ^ Shalom Feuerstein R. et al. Impaired epithelial differentiation of induced pluripotent stem cells from EEC patients is rescued by APR-246/PRIMA-1MET. P.N.A.S 2012. 存档副本. [2014-12-13]. (原始内容存档于2014-12-14). 
  18. ^ Shiran MS, Tan GC, Sabariah AR, Rampal L, Phang KS. p63 as a complimentary basal cell specific marker to high molecular weight-cytokeratin in distinguishing prostatic carcinoma from benign prostatic lesions. The Medical Journal of Malaysia. Mar 2007, 62 (1): 36–9. PMID 17682568. 
  19. ^ Herawi M, Epstein JI. Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate. The American Journal of Surgical Pathology. Jun 2007, 31 (6): 889–94. PMID 17527076. doi:10.1097/01.pas.0000213447.16526.7f. 
  20. ^ Zhang H, Liu J, Cagle PT, Allen TC, Laga AC, Zander DS. Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach. Modern Pathology. Jan 2005, 18 (1): 111–8. PMID 15309021. doi:10.1038/modpathol.3800251. 
  21. ^ Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T, Yuriditsky E, Trink B, Sidransky D, Ratovitski E. P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome. The Journal of Biological Chemistry. Jun 2003, 278 (26): 23906–14. PMID 12692135. doi:10.1074/jbc.M300746200. 
  22. ^ Yi R, Poy MN, Stoffel M, Fuchs E. A skin microRNA promotes differentiation by repressing 'stemness'. Nature. Mar 2008, 452 (7184): 225–9. PMID 18311128. doi:10.1038/nature06642. 
  23. ^ Aberdam D, Candi E, Knight RA, Melino G. miRNAs, 'stemness' and skin. Trends in Biochemical Sciences. Dec 2008, 33 (12): 583–91 [2017-11-13]. PMID 18848452. doi:10.1016/j.tibs.2008.09.002. (原始内容存档于2013-04-21). 

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