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<Structure load='2ZV6' size='350' frame='true' align='right' caption='Squamous cell carcinoma antigen 1 (PDB code [[2zv6]])' scene='Insert optional scene name here' />{{Sandbox_ESBS}}<!--
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'''<big>SQUAMOUS CELL CARCINOMA ANTIGEN 1</big>'''
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PLEASE ADD YOUR CONTENT BELOW HERE -->
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<StructureSection load='2ZV6' size='350' side='right' caption='Tridimensional structure of Squamous cell carcinoma antigen 1 (PDB code [[2zv6]])' scene=''>
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'''Squamous cell carcinoma antigen 1''' (SCCA1) is a tumor associated protein of squamous cell carcinoma of various organs. SCCA1 was originally purified from SCC of the uterine cervix <ref>Martz, E. Book review of ''Introduction to protein science—architecture, function, and genomics: Lesk, Arthur M. Biochem. Mol. Biol. Educ.'' 33:144-5 (2006). [http://link.springer.com/chapter/10.1007/978-1-4612-0401-5_21#page-1 DOI :10.1007/978-1-4612-0401-5_21#page-1]</ref>. SCCA1 is a [http://en.wikipedia.org/wiki/Tumor_marker tumor marker] to detect malignant tumor and to understand biological behaviors of squamous cells. SCCA1 is classified as a serine protease inhibitor called [http://en.wikipedia.org/wiki/Serpin serpin] B3. It also inhibits [http://en.wikipedia.org/wiki/Chymotrypsin chymotripsin], [http://en.wikipedia.org/wiki/Cathepsin cathepsin] L, K and S and papain like cysteine proteases. In the case of tumor development SCCA1 inhibits NK cells(natural killer), TNFalfa and apoptosis of tumor cells induced by treatment. It can also play a role in tumor growth. The chromosomal location is the locus 18q21.3.<ref>PMID:9817978</ref>
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==Squamous cell carcinoma antigen==
 
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==Structure==
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==Introduction==
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===General structure===
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Squamous cell carcinoma antigen is a tumor associated protein of squamous cell carcinoma of various organs. SCCA was originally purified from SCC of the uterine cervix <ref>Martz, E. Book review of ''Introduction to protein science—architecture, function, and genomics: Lesk, Arthur M. Biochem. Mol. Biol. Educ.'' 33:144-5 (2006). [http://link.springer.com/chapter/10.1007/978-1-4612-0401-5_21#page-1 DOI :10.1007/978-1-4612-0401-5_21#page-1]</ref>. SCCA is a [http://en.wikipedia.org/wiki/Tumor_marker tumor marker] to detect malignant tumor and to understand biological behaviors of squamous cells. SCCA is classified as a serine protease inhibitor called [http://en.wikipedia.org/wiki/Serpin serpin] B3. It also inhibits [http://en.wikipedia.org/wiki/Chymotrypsin chymotripsin], [http://en.wikipedia.org/wiki/Cathepsin cathepsin] L, K and S and papain like cysteine proteases. In the case of tumor development SCCA 1 inhibits NK cells(natural killer), TNFalfa and apoptosis of tumor cells induced by treatment. It can also play a role in tumor growth. The chromosomal location is the locus 18q21.3.<ref>PMID:9817978</ref>
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Serpins are a superfamily of proteins wich are functionally distinct but structurally conserved. <ref>JBC Papers in Press. Published on July 2, 2001 as Manuscript R100016200 THE SERPINS ARE AN EXPANDING SUPERFAMILY OF
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STRUCTURALLY SIMILAR BUT FUNCTIONALLY DIVERSE PROTEINS, http://www.jbc.org/content/early/2001/07/02/jbc.R100016200.full.pdf DOI : 2001/07/02/jbc.R100016200.full.pdf </ref>
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==General structure==
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SerpinB3 means serin protease inhibitor, clade B (for ovalbumin), member 3. The particularity of serpin B3 is to target proteases which have a nucleophilic cysteine instead of serine in their catalytic site.
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SCCA1 is a <scene name='60/604473/Trimeric/1'>trimeric protein</scene><ref> PMID : 19166818 </ref>. <scene name='60/604473/One_subunit/1'>One subunit</scene> has three β sheets termed <scene name='60/604473/A_beta_sheet/3'>A (7 stranded)</scene>, <scene name='60/604473/B_beta_sheet/2'>B (5 stranded)</scene> and <scene name='60/604473/C_beta_sheet/2'>C (6 stranded)</scene> and <scene name='60/604473/Alpha_helices/1'>11 α helices (hA to hK)</scene> <ref>Gary A. Silverman1*, Phillip I. Bird2
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Serpins are a superfamily of functionally distinct but structurally conserved proteins. <ref>JBC Papers in Press. Published on July 2, 2001 as Manuscript R100016200 THE SERPINS ARE AN EXPANDING SUPERFAMILY OF
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STRUCTURALLY SIMILAR BUT FUNCTIONALLY DIVERSE PROTEINShttp://www.jbc.org/content/early/2001/07/02/jbc.R100016200.full.pdf DOI : 2001/07/02/jbc.R100016200.full.pdf </ref>
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SerpinB3 means serin protease inhibitor, clade B (ovalbumin), member 3. The particularity of Serpin B3 is to target proteases wich have a nucleophilic cysteine instead of serine in their catalytic site.
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SCCA1 is a trimeric protein<ref> PMID : 19166818 </ref>
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. Like all for serpins, <scene name='60/604473/One_subunit/1'>one subunit</scene> has three β sheets termed <scene name='60/604473/A_beta_sheet/3'>A (7 stranded)</scene>, <scene name='60/604473/B_beta_sheet/2'>B (5 stranded)</scene> and <scene name='60/604473/C_beta_sheet/2'>C (6 stranded)</scene> and <scene name='60/604473/Alpha_helices/1'>11 α helices (hA to hK)</scene> <ref>Gary A. Silverman1*, Phillip I. Bird2
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, Robin W. Carrell3
, Robin W. Carrell3
, Frank C. Church4
, Frank C. Church4
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, Eileen RemoldO'Donnell9
, Eileen RemoldO'Donnell9
, Guy S. Salvesen10, James Travis11 and James C. Whisstock, THE SERPINS ARE AN EXPANDING SUPERFAMILY OF
, Guy S. Salvesen10, James Travis11 and James C. Whisstock, THE SERPINS ARE AN EXPANDING SUPERFAMILY OF
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STRUCTURALLY SIMILAR BUT FUNCTIONALLY DIVERSE PROTEINS, http://www.jbc.org/content/early/2001/07/02/jbc.R100016200.full.pdf DOI : 2001/07/02/jbc.R100016200.full.pdf </ref> <ref>PDB, Crystal structure of human squamous cell carcinoma antigen 1 http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2ZV6&bionumber=1 DOI : pdb/explore/remediatedSequence.do?structureId=2ZV6&bionumber=1</ref> .
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STRUCTURALLY SIMILAR BUT FUNCTIONALLY DIVERSE PROTEINS, http://www.jbc.org/content/early/2001/07/02/jbc.R100016200.full.pdf DOI : 2001/07/02/jbc.R100016200.full.pdf </ref> <ref>PDB, Crystal structure of human squamous cell carcinoma antigen 1 http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2ZV6&bionumber=1 DOI : pdb/explore/remediatedSequence.do?structureId=2ZV6&bionumber=1</ref>.
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The most important part of Serpins is an exposed region of 20 amino acids near the C terminus named the reactive center loop (<scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene>). The amino-acids of <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> are very conservated for Serpin B3 and allow the specificity interaction of the inhibitor for the target protease<ref> PMID : PMC24842</ref>.
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The most important domain of SCCA1 is an exposed region of 20 amino acids near the C terminal end named the reactive center loop (<scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene>). The amino-acids of <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> are very conservated for SCCA1 and allow the specificity interaction between the inhibitor and the target protease<ref> PMID : PMC24842</ref>.
===Conformational changes of serpins===
===Conformational changes of serpins===
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Structural studies on serpins revealed that inhibitory members of the family undergo an unusual conformational change, termed the Stressed to Relaxed (S to R) transition. During this structural transition the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> inserts into A β-sheet and forms an extra fourth β strand . The serpin conformational change is key to the mechanism of inhibition of target proteases. <scene name='60/604473/Rcl_insertion_into_beta_sheet/1'>Some amino-acids of RCL</scene> wich belong to a consensus sequence for inhibitory serpins are thought to permit efficient and rapid insertion of the RCL into the A β-sheet.<ref> James C Whisstocka, 2, Richard Skinnera, 2, Robin W Carrella, Arthur M Leska, Conformational changes in serpins: I. the native and cleaved conformations of α1-antitrypsin1, http://www.sciencedirect.com/science/article/pii/S0022283699935209 DOI:pii/S0022283699935209</ref>
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The inhibitory members of serpin family undergo an unusual conformational change, the Stressed to Relaxed transition. This structural transition causes the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> insertion into <scene name='60/604473/A_beta_sheet/3'>A β-sheet</scene> thereby the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> forms an extra β strand. The serpin conformational change is essential for the inhibitor mechanism of proteases. <scene name='60/604473/Rcl_insertion_into_beta_sheet/1'>Some amino-acids of RCL</scene> wich belong to a consensus sequence for inhibitory serpins are thought to permit the insertion of the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> into the <scene name='60/604473/A_beta_sheet/3'>A β-sheet</scene>.<ref> James C Whisstocka, 2, Richard Skinnera, 2, Robin W Carrella, Arthur M Leska, Conformational changes in serpins: I. the native and cleaved conformations of α1-antitrypsin1, http://www.sciencedirect.com/science/article/pii/S0022283699935209 DOI:10.1006/jmbi.1999.3520</ref>Key regions able to control and modulate the conformational change of RCL. The hinge which is the <scene name='60/604473/P9-p15/1'>P15-P9 portion of the RCL</scene> is responsible for the mobility which is essential during the conformational change in the Stress to Relax transition. The breach is situated in the top of the <scene name='60/604473/A_beta_sheet/3'>β-sheet</scene>. It is located at the point of initial insertion of the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> into the <scene name='60/604473/A_beta_sheet/3'>A β-sheet</scene>. The shutter is next to the <scene name='60/604473/A_beta_sheet/3'>A β-sheet</scene>. It facilitates the beta-sheet opening and accept the conserved hinge of the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> as it insert. The gate is fully inserted into the <scene name='60/604473/A_beta_sheet/3'>A β-sheet</scene> without cleavage, the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> has to pass around the β-turn linking strands.
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[[Image:Structure region.jpg|300px]] [[Image:Fontion3.jpg|400px]]
 
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==Fonction==
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[[Image:Structure region.jpg|center|thumbnail|300px|'''Key regions able to control and modulate the conformational change of RCL<ref>PMID :11116082</ref>''']]
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===Cysteine proteases mecanism===
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==Main SCCA1 function==
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When attacking a substrate, proteases catalyze peptide bond cleavage in a two-step process. Initially, the catalytic cysteine performs a nucleophilic attack on the peptide bond of the substrate. This releases the new N-terminus and forms an new bond between the enzyme and the substrate. This covalent enzyme-substrate complex is called an acyl enzyme intermediate. Subsequent to this, this bond is hydrolysed and the new C-terminus is released.
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===Cysteine proteases mechanism===
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When a cystein protease attacks a substrate, the peptide bond cleavage is catalyzed. Firstly, the catalytic cysteine performs a nucleophilic attack on the substrate peptide bond. Thus the new N-terminal end is released and a new bond between the enzyme and the substrate is created forming a covalent enzyme-substrate complex called the acyl enzyme intermediate. Finally, this new bond is hydrolysed and the new C-terminal end is released.
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http://en.wikipedia.org/wiki/Serpin
 
===Protease inhibition===
===Protease inhibition===
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The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> of a serpin acts as a substrate for its cognate protease.
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The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> of SCCA1 acts as a substrate for its target protease.
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The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> is cleaved at a scissile bond between two residues <scene name='60/604473/P1_scene/3'>Ser354 termed P1 (N-terminal of the cleavage event) and Ser355 termed P1’ (C-terminal of the cleavage event)</scene>. The P1 and P1' residues are critical for serpin specificity and mutation of these residues results in the loss or conversion of inhibitory activity. The protease recognize <scene name='60/604473/Amino_acids_for_protease_recog/1'>amino-acids of the RCL</scene> that allow its docking.
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The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> is cleaved at a scissile bond between two residues <scene name='60/604473/P1_scene/3'>Ser354 termed P1 (N-terminal of the cleavage site) and Ser355 termed P1’ (C-terminal of the cleavage site)</scene>. The <scene name='60/604473/P1_scene/3'>P1 and P1' residues</scene> are the necessary condition for target protease specificity. Indeed, the mutation of these residues results destroys inhibitory activity. The protease recognizes <scene name='60/604473/Amino_acids_for_protease_recog/1'>amino acids of the RCL</scene> that allow its docking.
<ref>M. S. J. Mangan, D. Kaiserman & P. I. Bird, The role of serpins in vertebrate immunity
<ref>M. S. J. Mangan, D. Kaiserman & P. I. Bird, The role of serpins in vertebrate immunity
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Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australiahttp://onlinelibrary.wiley.com/doi/10.1111/j.1399-0039.2008.01059.x/pdf DOI : 10.1111/j.1399-0039.2008.01059.x/pdf </ref> http://genome.cshlp.org/content/10/12/1845
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Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australiahttp://onlinelibrary.wiley.com/doi/10.1111/j.1399-0039.2008.01059.x/pdf DOI : 10.1111/j.1399-0039.2008.01059.x/pdf </ref> <ref>James A. Irving1, Robert N. Pike1, Arthur M. Lesk2, and James C. Whisstock1, Phylogeny of the Serpin Superfamily: Implications of Patterns of Amino Acid Conservation for Structure and Function, http://genome.cshlp.org/content/10/12/1845 DOI : content/10/12/1845</ref>
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[[Image:Fonction2.jpg|600px]] [[Image:fonction1.jpg|900px]]
 
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Prior to hydrolysis of the acyl-enzyme intermediate, the serpin rapidly undergoes the S-to-R transition. Since the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> is still covalently attached to the protease via the ester bond, the S-to-R transition moves the protease from the top to the bottom of the serpin. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0104935 At the same time, the protease is distorted into a conformation, where the acyl enzyme intermediate is hydrolysed extremely slowly. The protease thus remains covalently attached to the target protease and is thereby inhibited.
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[[Image:fonction1.jpg|center|thumbnail|750px|'''Mecanism of cathepsin S-inhibition by serpin B3''']]
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[[Image:Gb-2006-7-5-216-1-l_-_Copie.jpg|600px]]
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Before the hydrolysis of the acyl-enzyme intermediate, the serpin rapidly undergoes from Stressed to Relaxed transition. The <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> remains covalently attached to the protease, however the protease is moved from the top to the bottom of SCCA1. <ref> Sílvia Gomes, Patrícia I. Marques,Rune Matthiesen, Susana Seixas, Adaptive Evolution and Divergence of SERPINB3: A Young Duplicate in Great Apes,http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0104935 DOI : 10.1371%2Fjournal.pone.0104935</ref>
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This movement induces a protease distortion into a conformation, in which the acyl enzyme intermediate is hydrolysed extremely slowly. The active site of the enzyme would be expected to break.The protease thus remains covalently attached to the target protease and is thereby inhibited.
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Further, since the serpin has to be cleaved to inhibit the target protases, inhibition consumes the serpin as well. Serpins are therefore irreversible enzyme inhibitors.
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[[Image:Antitrypsin-rasmol.jpg|center|thumbnail|750px|'''Protease inhibition by SERPIN B3<ref>David Goodsell,Serpins, Molecule of the Month May 2004 ,http://www.rcsb.org/pdb/101/motm.do?momID=53 DOI: 10.2210/rcsb_pdb/mom_2004_5</ref>''']]
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Consequently, the serpin has to be cleaved to inhibit the target proteases. SCCA1 is irreversible protease inhibitor.
<ref>J. A. HUNTINGTON,Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK, Serpin structure, function and dysfunction,
<ref>J. A. HUNTINGTON,Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK, Serpin structure, function and dysfunction,
http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2011.04360.x/pdf DOI : 10.1111/j.1538-7836.2011.04360.x/pdf</ref>
http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2011.04360.x/pdf DOI : 10.1111/j.1538-7836.2011.04360.x/pdf</ref>
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The increase of the SCCA1 residing in the cytosol of squamous carcinoma cell may protect the tumor by neutralizing harmful proteases.
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The increase of the SCCA1 in the cytosol of squamous carcinoma cell may protect the tumor by neutralizing harmful proteases.
== The SCCA1 a tumor marker ==
== The SCCA1 a tumor marker ==
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Tumor markers are compounds present in abnormal concentration in serum or urine in patients who develop a malignant tumor. Nevertheless tumor markers can appear in people who do not suffer from cancer or at low concentration in sick patients, this is called the false negative or false positive. Tumor markers are used to detect, prevent, diagnose, predict, determine, prognostic and therapeutic monitoring. Tumor markers need to be specific and sensitive. The dosage of several markers is necessary to establish the success or the failure of a treatment.
Tumor markers are compounds present in abnormal concentration in serum or urine in patients who develop a malignant tumor. Nevertheless tumor markers can appear in people who do not suffer from cancer or at low concentration in sick patients, this is called the false negative or false positive. Tumor markers are used to detect, prevent, diagnose, predict, determine, prognostic and therapeutic monitoring. Tumor markers need to be specific and sensitive. The dosage of several markers is necessary to establish the success or the failure of a treatment.
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The SCCA is secreted by the tumor itself, it is a marker of mature cells. The SCCA is a glycoprotein present in the epithelium cells and released in the serum during epidermoid cervical cancer but also in epidermoid cancers suchh as lung, mouth, larynx, pharynx and esophagus. The cooncentration threshold is inferior at 1.5 µg for healthy patient.<ref>L. P. Kerbrat, Que faire des marqueurs tumoraux, Centre Eugène Marquis, Université de Rennes 1 [https://facmed.univ-rennes1.fr/wkf/stock/RENNES20110504094607cpiszkormarqueurs_tumoraux.coursDCEM1-02-2011.pdf DOI : stock/RENNES20110504094607cpiszkormarqueurs_tumoraux.coursDCEM1-02-2011.pdf]</ref>
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The SCCA1 is secreted by the tumor itself, it is a marker of mature cells. The SCCA1 is a glycoprotein present in the epithelium cells and released in the serum during epidermoid cervical cancer but also in epidermoid cancers such as lung, mouth, larynx, pharynx and esophagus. The concentration threshold is inferior at 1.5 µg for healthy patient.<ref>L. P. Kerbrat, Que faire des marqueurs tumoraux, Centre Eugène Marquis, Université de Rennes 1 [https://facmed.univ-rennes1.fr/wkf/stock/RENNES20110504094607cpiszkormarqueurs_tumoraux.coursDCEM1-02-2011.pdf DOI : stock/RENNES20110504094607cpiszkormarqueurs_tumoraux.coursDCEM1-02-2011.pdf]</ref>
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===SCCA role as a tumor marker===
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===SCCA1 role as a tumor marker===
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SCCA is particularly used for the detecction of cancer of the uterine cervix. The correlation between SCCA concentration and lung tumor was proved. SCCA concentration increases in the presence of epidermoid lung tumor, independently of the differentiation state of the tumor<ref>PMID:1620906</ref>. SCCA is especially used to prognostic and follow the effects of the treatment in the lung cancer as second tumor marker <ref> Les marqueurs tumoraux Tableau d’aide à la description des principaux marqueurs tumoraux, Ketterhill laboratoires d’analyses médicales [http://www.llam.lu/fileadmin/media/newsletter/Marqueurs_Tum.pdf DOI : newsletter/Marqueurs_Tum.pdf] </ref>
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SCCA1 is particularly used for the detection of cancer of the uterine cervix. The correlation between SCCA1 concentration and lung tumor was proved. SCCA1 concentration increases in the presence of epidermoid lung tumor, independently of the differentiation state of the tumor<ref>PMID:1620906</ref>. SCCA1 is especially used to prognostic and follow the effects of the treatment in the lung cancer as second tumor marker <ref> Les marqueurs tumoraux Tableau d’aide à la description des principaux marqueurs tumoraux, Ketterhill laboratoires d’analyses médicales [http://www.llam.lu/fileadmin/media/newsletter/Marqueurs_Tum.pdf DOI : newsletter/Marqueurs_Tum.pdf] </ref>. High concentration of SCCA1 in the blood suggests the epithelial cells direct serpin activity to blood. This pathway is an active secretory process<ref>PMID:10956412</ref>.
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. High concentration of SCCA in the blood suggests the epithelial cells direct serpin activity to blood. This pathway is an active secretory process<ref>PMID:10956412</ref>.
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===SCCA and cancer===
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===SCCA1 and cancer===
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SCCA is not specific of one type of cancer. It can be associated to mild broncho-pulmonarypathology, mild skin pathology. It does not depend on Tobacco consumption. SCCA is associated to cancer and non-malignant kidney pathology. It is quantified by immuno-analyzes, its half-life is 3 days.
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SCCA1 is not specific of one type of cancer. It can be associated to mild broncho-pulmonarypathology, mild skin pathology. It does not depend on Tobacco consumption. SCCA1 is associated to cancer and non-malignant kidney pathology. It is quantified by immuno-analyzes, its half-life is 3 days.
-In cervix cancer :
-In cervix cancer :
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The SCCA increase is linked to the tumor weight and state of disease. Nevertheless 40 % of patients suffering from cervix cancer have a high SCCA blood concentration, it is not use for screening. An increase of the initial rate can be a sign of disease recurrence or persistence. It allows to follow the treatment efficiency such as chemotherapy, radiotherapy in patients.
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The SCCA1 increase is linked to the tumor weight and state of disease. Nevertheless 40 % of patients suffering from cervix cancer have a high SCCA1 blood concentration, it is not use for screening. An increase of the initial rate can be a sign of disease recurrence or persistence. It allows to follow the treatment efficiency such as chemotherapy, radiotherapy in patients.
-In epidermoid bronchopulmonary cancer :
-In epidermoid bronchopulmonary cancer :
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SCCA is not used for screening. <ref>Micke O, Prott FJ, Schäfer U, Tangerding S, Pötter R, Willich N.The impact of squamous cell carcinoma (SCC) antigen in the follow-up after radiotherapy in patients with cervical cancer. Anticancer Res 2000 ; 20 : 5113-5115. National Academy of Clinical Biochemistry.Guidelines for the Use of Tumor Markers in cervical cancer.[//www.nacb.org/lmpg/tumor/chp3j_cervical.d DOI : tumor/chp3j_cervical.d]</ref>
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SCCA1 is not used for screening. <ref>Micke O, Prott FJ, Schäfer U, Tangerding S, Pötter R, Willich N.The impact of squamous cell carcinoma (SCC) antigen in the follow-up after radiotherapy in patients with cervical cancer. Anticancer Res 2000 ; 20 : 5113-5115. National Academy of Clinical Biochemistry.Guidelines for the Use of Tumor Markers in cervical cancer.[//www.nacb.org/lmpg/tumor/chp3j_cervical.d DOI : tumor/chp3j_cervical.d]</ref>
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=Interaction=
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=Interactions of SCCA1 involved in diseases=
===Hepatite B virus (HBV) interaction===
===Hepatite B virus (HBV) interaction===
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The SCCA may play a role of cellular receptor for hepatitis B virus. The SCCA expression enhances the binding and internalization of hepatitis B virus with hepatocyte or non-hepatocytes origin cells. The transfection of SCCA in hepatocyte generates more viruses DNA in infected cells. Besides the virus bound to transfected cell is protected against degradation by trypsin thanks to a partial internalization. The binding between HBV and hepatocytes is more marked than for the others types of cells like COS-7 (kidney cells of monkey transformed by antibody T of SV40). The binding complex of cells COS-7 with HBV seems to be more complex. The low density lipoprotein receptor-related protein (LRP) mediates the clearance of serpin-enzyme complex, the LRP may not enhance virus binding to transfected cells. SCCA may be a co-receptor for HBV, virus binding to the transfected cells doesn’t depend on the proteinase inhibitor function or the interaction receptor LRP but it may depend on <scene name='60/604473/The_rcl_loop_scene/3'>the reactive site loop</scene> of SCCA. <ref>Penelope L. Moore‡, Sarah Ong, and Tim J. Harrison§, Squamous Cell Carcinoma Antigen 1-mediated Binding of Hepatitis B Virus to Hepatocytes Does Not Involve the Hepatic Serpin Clearance System*[http://www.jbc.org/content/278/47/46709.full DOI 47/46709.full]</ref>
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The SCCA1 may play a role of cellular receptor for hepatitis B virus. The SCCA1 expression enhances the binding and internalization of hepatitis B virus with hepatocyte or non-hepatocytes origin cells. The transfection of SCCA1 in hepatocyte generates more viruses DNA in infected cells. Besides the virus bound to transfected cell is protected against degradation by trypsin thanks to a partial internalization. The binding between HBV and hepatocytes is more marked than for the others types of cells like COS-7 (kidney cells of monkey transformed by antibody T of SV40). The binding complex of cells COS-7 with HBV seems to be more complex. The low density lipoprotein receptor-related protein (LRP) mediates the clearance of serpin-enzyme complex, the LRP may not enhance virus binding to transfected cells. SCCA may be a co-receptor for HBV, virus binding to the transfected cells doesn’t depend on the proteinase inhibitor function or the interaction receptor LRP but it may depend on <scene name='60/604473/The_rcl_loop_scene/3'>the reactive site loop</scene> of SCCA1. <ref>Penelope L. Moore‡, Sarah Ong, and Tim J. Harrison§, Squamous Cell Carcinoma Antigen 1-mediated Binding of Hepatitis B Virus to Hepatocytes Does Not Involve the Hepatic Serpin Clearance System*[http://www.jbc.org/content/278/47/46709.full DOI 47/46709.full]</ref>
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===JUNK1 interaction===
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===JNK1 interaction===
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SCCA1 also acts as an inhibitor of UV-induced apoptosis via suppression of the activity of c-Jun NH(2)-terminal kinase (JNK1). It is known that JNK1 is responsible for UV-induced apoptotic cell death and SCCA-1 is up-regulated in UV-irradiated and sun-exposed cells. SCCA1 binds to phosphorylated JNK1 and is transferred into the nucleus after UV irradiation.
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SCCA1 acts as an inhibitor of UV-induced apoptosis by suppressing the activity of JNK1 (c-Jun NH2-terminal kinase). It is known that JNK1 is responsible for UV-induced apoptotic cell death and SCCA-1 is up-regulated in UV-irradiated and sun-exposed cells. SCCA1 binds to phosphorylated JNK1 and is transferred into the nucleus after UV irradiation.
<ref>Chika Katagiri, Jotaro Nakanishi, Kuniko Kadoya, and Toshihiko Hibino, Serpin squamous cell carcinoma antigen inhibits
<ref>Chika Katagiri, Jotaro Nakanishi, Kuniko Kadoya, and Toshihiko Hibino, Serpin squamous cell carcinoma antigen inhibits
UV-induced apoptosis via suppression of c-JUN
UV-induced apoptosis via suppression of c-JUN
NH2-terminal kinase
NH2-terminal kinase
http://jcb.rupress.org/content/172/7/983.full.pdf+html DOI : 172/7/983.full.pdf+html </ref>
http://jcb.rupress.org/content/172/7/983.full.pdf+html DOI : 172/7/983.full.pdf+html </ref>
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Indeed the reactive center loop (<scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene>) of SCCA1 is very flexible and located away from the center of SCCA1. The inhibitory effect of SCCA1 on the kinase activity of JNK1 is lost when the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> was truncated. Furthermore, a mutant protein created by replacing one amino acid in <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> maintain the suppressive activity to JNK1, whereas the inhibitory effect to proteinase is obviously decreased.
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Indeed the (<scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene>) of SCCA1 is an external and flexible domain of SCCA1. When the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> is truncated, the inhibitory effect of SCCA1 on the kinase activity of JNK1 is lost.
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<ref> PMID : 19166818<ref>
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Moreover, a mutant protein created by replacing <scene name='60/604473/Phe_352/1'>one amino-acid</scene> in <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> even retains the suppressive activity against JNK1 but the inhibitory proteinase activity is reduced. This indicates that exposed <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> is essential for the JNK1 inhibitory activity and that JNK1 interaction site is different from the protease site. Actually, JNK1 may binds the <scene name='60/604473/The_rcl_loop_scene/3'>RCL</scene> region, excepting the protease binding site, or the center of <scene name='60/604473/A_beta_sheet/3'>A β-sheet</scene>. <ref> PMID : 19166818</ref>
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===Receptor (LPR) interaction===
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The serpin and serpin-protease complexes are able to bind the low density lipoprotein receptor-related protein (LPR). This binding allow to clear serpin- complexes from blood circulation. The ligand bind a clusters of rich cysteine residues. No differences were noticed between native and cleaved serpin. The binding between serpin and enzyme such as protease may increase the affinity of the complexe for LPR <ref>PMID: PMC2709341</ref>
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= Disease =
= Disease =
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Asthma is characterized by an obstruction of the interior respiratory tract and an excessive mucus secretion.<ref>Santé médecine, Hyperplasie définition[http://sante-medecine.commentcamarche.net/faq/13479-hyperplasie-definition DOI : faq/13479-hyperplasie-definition]</ref> Experiments were performed on mice, mice lacking SerpinB3 showed a decrease of the mucus secretion. As a result serpinB3 may have a role in mucus hypersecretion in a house dust mist model of asthma. The SPDEF ( SAM pointed domain containing ETS transcription factor) expression causes the hyperplasia of goblet cell. The hyperplasia designates the abnormal augmentation of cells number in a tissue, the subexpression of goblet cells m ay induce cancer. Serpin B3 increase SPDEF expression and goblet cells hyperplasia. <ref> PMID: 3058372 </ref>
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Asthma is characterized by an obstruction of the interior respiratory tract and an excessive mucus secretion.<ref>Santé médecine, Hyperplasie définition[http://sante-medecine.commentcamarche.net/faq/13479-hyperplasie-definition DOI : faq/13479-hyperplasie-definition]</ref> Experiments were performed on mice, mice lacking serpinB3 showed a decrease of the mucus secretion. As a result serpinB3 may have a role in mucus hypersecretion in a house dust mist model of asthma. The SPDEF (SAM pointed domain containing ETS transcription factor) expression causes the hyperplasia of goblet cell. The hyperplasia designates the abnormal augmentation of cells number in a tissue, the subexpression of goblet cells m ay induce cancer. Serpin B3 increase SPDEF expression and goblet cells hyperplasia. <ref> PMID: 3058372 </ref>
= Regulation =
= Regulation =
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The E-cadherin can regulate the SCCA production in the squamous cell carcinoma of the uterin cervix. E-cadherins are transmembrane proteins, they have a role in cell adhesion because they are able to form adherens junctions. They have to bind a Ca++ ion to work. Using an anti-E-cadherin antibody induces the dissociation of the cervical squamous cell carcinoma. It also induces a decrease of SCCA in the cytosol and SCCA m RNA. Besides the phosphatidyl inositol 3 kinase is a mediator of E-cadherin. The E-cadherin mediates cell-cell adhesion and maintains SCCA production thanks to phosphatidyl inositol 3 kinase in squamous cell carcinoma.<ref> PMID: 14719077 </ref>
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The E-cadherin can regulate the SCCA1 production in the squamous cell carcinoma of the uterin cervix. E-cadherins are transmembrane proteins, they have a role in cell adhesion because they are able to form adherens junctions. They have to bind a Ca++ ion to work. Using an anti-E-cadherin antibody induces the dissociation of the cervical squamous cell carcinoma. It also induces a decrease of SCCA1 in the cytosol and SCCA1 mRNA. Besides the phosphatidyl inositol 3 kinase is a mediator of E-cadherin. The E-cadherin mediates cell-cell adhesion and maintains SCCA1 production thanks to phosphatidyl inositol 3 kinase in squamous cell carcinoma.<ref> PMID: 14719077 </ref>
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</StructureSection>
 
= References =
= References =
<references/>
<references/>

Current revision

SQUAMOUS CELL CARCINOMA ANTIGEN 1

Tridimensional structure of Squamous cell carcinoma antigen 1 (PDB code 2zv6)

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