Testin, TESS, 或Tes，一種被第七染色體上的Tes基因編輯形成的蛋白質。Tes是一個在焦點粘連處被發現的由421個胺基酸組成的47 kDa的蛋白質；對管理細胞活性有一定的影響。同時也對腫瘤的發展有一定的抑制作用。Tes基因位於第七染色體薄弱位置，2007年確認它有腫瘤抑制功能使之名聲大旺。
基本介紹
- 中文名：臨床診斷激素值TES
- 外文名：Testin
TES as a tumour suppressor[edit],Conformational Change[edit],Phenotype[edit],
Testinalso known asTESSis aproteinthat in humans is encoded by theTESgenelocated onchromosome7.TES is a 47kDaprotein composed of 421amino acidsfound atfocal adhesionsand is thought to have a role in regulation ofcell motility.In addition to this, TES functions as atumoursuppressor.TheTESgene is located within a fragile region ofchromosome 7, and thepromoterelements of theTESgene have been shown to be susceptible tomethylation- this prevents theexpressionof the TES protein. TES came to greater prominence towards the end of 2007 as a potential mechanism for itstumour suppressor functionwas published.
TES as a tumour suppressor[edit]
In December 2007, Boeda, Briggset al.showed that the third LIM domain of TES displaces Mena from its usual subcellular positions (focal adhesionsor the cell leading edge). The ENA/VASP protein family (of which Mena is a member) are anchored to specific proteins within the cell by apeptidemotif consisting of aphenylalanineresidue, followed by fourprolineresidues - known as a FPPPP motif. It is theEVH1 domainsof VASP/EVL proteins that directly contact the FPPPP motif. The precise architecture of TES:MENA binding was revealed byX-ray crystallography, and showed that the 3rd LIM domain of TES covered up the FPPPP binding site within Menas EVH1 domain.Isothermal titration calorimetryshowed that TES has a greater affinity for Mena than its canonical FPPPP ligand, as presented in the focal adhesion protein zyxin. Using microscopy it was shown that either over-expression ofGFP-tagged TES, or just the tagged third LIM domain displaced Mena from focal adhesions and reduced mean cell velocity.
These finding were significant given that Mena is often over-expressed incancercells, and is thought to be partly responsible for cancer cell motility, and therefore a factor in cancermetastasis. TES is conversely often not produced in cancer cells. It is possible that a drug designed to mimic TES's interaction with Mena could be used to prevent metastasis and thus development of secondary tumours in cancer patients. The work was widely reported in the British press (the work was carried out byCancer Research UK),and also in the international press.
Conformational Change[edit]
Based on the observations that:
- Mammalian cell derived TES binding Zyxin
- E. coliproducedrecombinantTES (rTES) does not bind Zyxin
- An rTES construct composed of residues 201-421 (i.e., the linker and all 3 LIM domains) does bind Zyxin
- The above rTES construct binds an N-terminal rTES construct, consisting of the cysteine rich and PET domains -IE, the two halves of TES interact with each other.
Garvalovet al.propose that TES exists in two conformational states: A 'closed' state where the N & C halves of TES interact, obscuring the Zyxin binding site in LIM1, and an 'open' state where the Zyxin binding site is accessible and the two halves no-longer interact in the same fashion, if at all. The regulatory mechanism switching between the two states is not presently fully understood.
Phenotype[edit]
InRNAiexperiments, cells that had impaired TES expression showed an inability to correctly organise theirfocal adhesionsandactinstress fibres.
In gene knockout experiments,transgenicmice lacking both copies of the TES gene displayed an increased susceptibility totumourformation when challenged with a carcinogen. Mice retaining the TES gene were less susceptible: thus, TES is a tumour suppressor gene.
