摘要
真核生物细胞中蛋白质降解参与新陈代谢、细胞分裂周期进程、对淋巴细胞的抗原提呈和许多其它重要功能的调节。泛素-蛋白酶体系统(ubiquitin-proteasome system，UPS)负责细胞中许多调控蛋白的降解。26S蛋白酶体是一2.5 MDa的巨大蛋白质复合物，由一个具有蛋白质降解活性的20S蛋白酶体(core particle，CP)和两个结合在20S蛋白酶体两个末端的19S调节颗粒(regulatory particles，RP)组成。除了已确定的蛋白酶体亚基外，近年来许多与蛋白酶体相关的、起着辅助作用的分子被鉴定。许多蛋白酶体研究是用酵母细胞来实现的，尤其是芽殖酵母。到目前为止，绝大部分酵母蛋白酶体亚基对应的哺乳动物蛋白酶体亚基已经被鉴定出来。为进一步确定哺乳动物蛋白酶体的组份和相关调节蛋白质，邱小波教授等人改良了基于亲和纯化的方法来快速从哺乳动物细胞中纯化26S蛋白酶体。用此方法，他们发现了一个新的45 kDa(407个氨基酸残基)的19S调节复合物的亚基命名为hRpn13(以前研究中将之称为ADRM1或GP110)。hRpn13能通过N-端部分(Δ201-407)与26S蛋白酶体结合，通过C-端部分(Δ1-200)与去泛素化酶UCH37结合。以前的研究报道表明hRpn13／ADRM1／GP110是一个高度糖基化的膜蛋白(110 kDa)并参与调节细胞粘附。Rpn13是hRpn13在芽殖酵母中的同源物，它与爪蟾胚胎发育所必须的Xoom(404个氨基酸的蛋白质)在N-端高度同源，而Xoom在爪蟾胚胎发育过程中发挥重要作用。
本研究是在邱小波教授等研究的基础之上进行的。经生物信息学分析表明hRpn13在真核细胞中高度保守，与酵母蛋白酶体亚基Daq1／Rpn13是同源基因，在细胞中可能有多种相互作用蛋白，并且可能发挥多种不同的功能。ADRM1／hRpn13在小鼠不同组织中的表达谱实验表明，ADRM1／hRpn13在所检测的小鼠各组织中均能表达，并且在睾丸、脑、胰腺、脾等组织中呈相对较高的表达。脑、胰腺、肝、肌肉和心脏等组织中存在一些迁移缓慢的ADRM1／hRpn13，推测其可能存在翻译后修饰。前期实验表明，hRpn13与蛋白酶体相关的蛋白质UCH37(ubiquitin carboxy-terminalhydrolase 37，去泛素化酶／异肽酶)相互作用。为更进一步确定两者的相互作用关系，我们构建了相关表达载体，用原核系统表达并纯化了His-hRpn13、His-hRpn13-C(Δ1-200)、GST-UCH37、GST-UCH37-N(A227-329)、GST-UCH37-C(Δ1-226)和His-S5a等蛋白质。GST pull down实验表明，当纯化的His-hRpn13与GST-UCH37、GST-UCH37-N(Δ227-329)和GST-UCH37-C(Δ1-226)一同孵育时，UCH37的全长和不保守的C-端延伸部分(Δ1-226)能与hRpn13共沉淀，而GST-UCH37-N(Δ227-329)则不能，表明UCH37通过C端与hRpn13结合，并且是与hRpn13的C-端部分(Δ1-200)结合。同样，我们将纯化的GST-UCH37与His-S5a共同孵育，结果发现UCH37能与S5a在体外结合，而作为对照的GST蛋白则不能与S5a结合。因此，在蛋白酶体中hRpn13和S5a均能与UCH37结合，它们可能是通过互补的机制将UCH37募集到蛋白酶体的。
文献报道UCH37是26S蛋白酶体中19S复合物中的一个去泛素化酶／异肽酶。明确了hRpn13与UCH37的相互作用后，我们进一步研究了hRpn13对UCH37去泛素化酶活性的影响。作为阳性对照，当昆虫细胞中纯化的His-hRpn13与UCH37共同孵育时，发现UCH37水解Ub-amc荧光底物的活性增加。采用原核表达纯化的全长hRpn13与UCH37共同孵育时，我们发现UCH37水解Ub-amc荧光底物的活性增加了69％。在相同条件下，原核表达纯化的hRpn13的C-端部分(Δ1-200)对UCH37的活性却无明显影响。
另外，邱小波教授等人发现hRpn13的C-端部分(Δ1-200)能引起细胞死亡。为了阐述该现象的机制，我们测试了hRpn13的C-端部分(Δ1-200，该部分不与蛋白酶体结合)能否与全长的hRpn13结合。GST pull down实验结果表明，与UCH37不同，全长hRpn13不能在体外与hRpn13的C-端部分(Δ1-200)结合。因此，hRpn13的C-端部分(Δ1-200)引起细胞死亡，可能是通过阻止UCH37而不是hRpn13结合到蛋白酶体上的机制。
综上所述，在哺乳动物26S蛋白酶体中，hRpn13将UCH37募集到蛋白酶体的19S复合物中，它通过N-端与蛋白酶体结合，通过C-端与UCH37结合，在UCH37和蛋白酶体之间起到非常重要的桥梁作用，并且hRpn13能增强UCH37的去泛素化酶的活性。
YWK-Ⅱ蛋白是一种Ⅰ型精子膜蛋白，最初是由本组采用一株抗人精子蛋白的单克隆抗体(YWK-Ⅱ)对大鼠睾丸λgt11 cDNA文库进行筛选获得的，定位于人精子头部的赤道区。序列分析发现YWK-Ⅱ蛋白与Alzheimer's病(老年性痴呆)相关的A4蛋白前体(APP)存在广泛的同源性和区域保守性，胞内区和跨膜区有70.6％的同源性。其后自人胎盘中筛选的该蛋白被命名为淀粉样蛋白前体同源蛋白(APPH)，并发现与大鼠淀粉样蛋白前体样蛋白2(APLP2)非常相似，为同一蛋白在不同种属中的不同形式。体外研究发现，重组表达的YWK-Ⅱ蛋白／APLP2胞内段能够被PKC和cdc2激酶磷酸化，并可以和GTP结合蛋白G_o蛋白相互作用，表明YWK-Ⅱ蛋白／APLP2可能是一种与G_o蛋白耦联的受体。采用酵母双杂交系统，发现YWK-Ⅱ蛋白／APLP2与穆勒氏管抑制性物质(Mullerianinhibiting substance，MIS)存在相互作用。YWK-Ⅱ蛋白／APLP2与MIS的相互作用已经GST Pull-down实验和表面等离子共振实验(SPR)在体外进行了验证。文献报道，MIS在成熟精子上存在结合位点，但没有证据显示，该结合位点即MIS的Ⅱ型受体，也没有证据显示，精子中有已知的MIS的Ⅱ型受体的表达。MIS的功能是多方面的，已发现其可在体外促进人精子的存活力和活动力，但与其相关的受体和信号通路仍不清楚。根据以上数据，我们推测MIS可能首先与YWK-Ⅱ蛋白／APLP2相互作用，通过G_o蛋白介导信号传导通路，引起人精子的存活力和活动力。
本研究的前期工作中，采用细胞膜表达YWK-Ⅱ蛋白／APLP2细胞模型，我们发现YWK-Ⅱ蛋白／APLP2通过与MIS和G_o蛋白相互作用，作为介导MIS引起细胞存活的受体。然而，MIS对精子这种影响的机制仍不清楚，因为精子中可能不存在MIS的Ⅱ型受体。因此，我们提出假设，YWK-Ⅱ蛋白／APLP2可能是G_o耦联的介导MIS引起精子细胞存活作用的受体。本研究在此基础上，分析了以下几个问题：1)证明了CHO细胞、COS-7细胞及人精子中均无MISR的Ⅱ型受体(MISRⅡ)的表达，提示COS-7细胞与CHO细胞一样可用于研究YWK-Ⅱ蛋白／APLP2作为MIS受体的细胞模型；人精子可用于今后的动物体内实验。2)MIS可引起过表达YWK-Ⅱ蛋白／APLP2的COS-7细胞中ERK1／2信号通路的激活，与CHO细胞模型的结果一致，表明YWK-Ⅱ蛋白／APLP2作为受体介导MIS引起的ERK1／2活化具有一定的普遍性。3)经MIS处理的过表达YWK-Ⅱ蛋白／APLP2的CHO细胞，p53表达水平下降，pro-caspase-3表达增强；YWK-Ⅱ抗体则可减弱后者的表达。提示YWK-Ⅱ蛋白／APLP2作为受体介导MIS增强细胞存活可能是通过抗凋亡机制。此外，应用组织芯片技术验证了YWK-Ⅱ蛋白／APLP2在胰腺癌组织中较正常胰腺组织中的表达增强，提示YWK-Ⅱ蛋白／APLP2可能参与胰腺癌的发生发展过程，为发掘YWK-Ⅱ蛋白／APLP2在肿瘤免疫治疗中的应用价值奠定基础。
Protein degradation in eukaryotic cells is involved in regulation of metabolism, progression through the cell division cycle, antigen presentation to lymphocytes and other important functions. The ubiquitin-proteasome system (UPS) is responsible for much of the regulated proteolysis in the cell. The 26S proteasome is a huge protein complex of approximately 2.5 MDa composed of one proteolytically active 20S proteasome and two 19S regulatory particles (RP), each attached to one end of the 20S proteasome. In addition to the genuine proteasome subunits, several molecules that associate with proteasomes and play auxiliary roles have been identified. Most of the proteasome studies have been carried out using yeast cells, especially budding yeasts. To date, most mammalian proteasomes and the counterparts of yeast proteasome subunits have been identified. To better define its composition and associated regulatory proteins, Qiu et al developed affinity methods to rapidly purify 26S proteasomes from mammalian cells. By this approach, they discovered a novel 45 kDa (407 residues) subunit of its 19S regulatory complex, hRpn13 (previously termed ADRM1 or GP110), which was previously reported as a heavily glycosylated membrane protein and regulates cell adhesion. It can be incorporated into the 26S proteasome by its N-terminal half and bind directly to the proteasome-associated deubiquitinating enzyme (DUBs), UCH37, by the C-terminal half. Yeast proteasome subunit Daq1/Rpn13, an ortholog of hRpn13, is highly homologous to the N-terminal Xoom, a 404 amino-acid protein required for the embryonic development of frogs.
Here we report hRpn13 is homologous to yeast Daq1/Rpn13 and conserved in eukaryotes, which may have many binding partners and be involved in many biological functions. ADRM1/hRpn13 is expressed in various mouse tissues examined by Western blot, especially higher in testis, brain, pancreas and spleen. Interestingly, higher molecular weight bands were detected in several tissues, including brain, pancreas, liver, heart and skeletal muscle, probably because of the post-translational modifications of ADRM1/hRpn13. By GST pull down assay, Qiu et al found that the C-terminal half of hRpn13 binds directly to the proteasome-associated deubiquitinating enzyme (DUBs), UCH37. To confirm the interaction between hRpn13 and UCH37, we constructed and expressed His-hRpn13 and its C-terminal half, the full-length GST-fusion UCH37 and two truncated proteins: GST-UCH37-N-terminal (A227-329) and GST-UCH37-C-terminal (△1-226) in E. coli. When purified, His-hRpn13 was incubated with either truncated or the full-length GST-UCH37, both the full-length and the C-terminal half, but not the N-terminal half of UCH37, could pull down hRpn13. That is, UCH37, through its C-terminal half, binds to the C-terminal half of hRpn13. When purified GST-UCH37 was incubated with purified His-tagged S5a, S5a could be pulled down by GST-UCH37, but not GST, suggesting that UCH37 binds to S5a. Thus, there are two, probably complementary, mechanisms by which UCH37 can be recruited to the proteasome.
It is reported that UCH37 acts as a deubiquitylating enzyme and we then investigate the effect of hRpn13 in activity of the deubiquitylating enzyme, UCH37. As a positive control, His-tagged hRpn13 (purified in insect cells by Qiu et al) could significantly promote the activity of UCH37. Then the purified full-length hRpn13 from E. coli was incubated with purified UCH37, the hydrolysis of Ub-amc by UCH37 increased by 69%. In contrast, under similar conditions, the C-terminal half of hRpn13 had no effect on the activity of UCH37.
Qiu et al showed that the C-terminal half of hRpn13 appears to induce cell death. In order to clarify the mechanism of this effect, we asked whether the C-terminal half of hRpn13 (which itself does not bind to the proteasome) might interact with full-length hRpn13. GST pull-down assays demonstrated that unlike UCH37, hRpn13 did not bind to its C-terminal half in vitro. Thus, the C-terminal half of hRpn13 induces cell death, probably by preventing UCH37, but not hRpn13, from binding to the proteasome.
Thus in human 26S proteasomes, hRpn13 appears to be important for the recruiting of UCH37, the proteasome-associated deubiquitinating enzyme, to the 19S complex (its N-terminal half can be incorporated into the 26S proteasome and the C-terminal half of hRpn13 binds directly to UCH37), as a bridge between UCH37 and the proteasome, and enhances its isopeptidase activity.
YWK-Ⅱprotein is a typeⅠsperm membrane protein which was initially identified as the target antigen to a monoclonal antibody (mAb) raised against proteins extracted from human sperm and was found to localize on the equatorial sector of human sperm head. It is highly homologous to the Amyloid Protein Precursor (APP) which is related to Alzheimer's desease, containing a segment with high homology (70.6%) to the transmembrane-cytoplasmic region of APP. The protein is subsequently referred to as the human placenta amyloid precursor protein homologue (APPH) and more similar to rat amyloid precursor like- protein 2 (APLP2), which are apparently species-specific forms of the same component. In vitro study demonstrates that the recombinant polypeptide of the cytoplasmic region of YWK-Ⅱprotein/APLP2 can be phosphorylated by PKC and cdc2 kinase and interacts with the GTP-binding protein G_o. The coupling of the polypeptide and G_o protein suggests that the YWK-Ⅱprotein/APLP2 is more like a G_o-coupled receptor and facilitates the G_o-mediated signal transduction pathway in germ cells undergoing differentiation and gamete interaction. It was found that YWK-Ⅱprotein/APLP2 can interact with Mullerian Inhibiting Substance (MIS) in yeast two-hybide system. The interaction between YWK-Ⅱprotein/APLP2 and MIS was verified by GST Pull-down assay and Surface Plasmon Resonance (SPR) in vitro. It was found that there are binding sites of MIS on mature sperm; however, there is no evidence shown that MIS typeⅡreceptor (MISRⅡ) is expressed on sperm. Mullerian inhibiting substance (MIS) has recently been implicated in multiple cellular functions including promotion of cell survival, but the receptor(s) and signaling pathways involved remain elusive. We suppose that MIS may initially interact with the YWK-Ⅱprotein/APLP2 and affect the motility and viability of human sperm by stimulating the G_o-mediated signal transduction pathway subsequently.
In a previous study, we have investigated the possibility of YWK-Ⅱprotein/APLP2, previously shown to interact physically with MIS and G_o protein, being a receptor mediating the cell survival effect of MIS. However, the mechanism of action of MIS on sperm remains unclear since an MIS typeⅡreceptor has not been shown to be present in germ cells. We thus hypothesized that YWK-Ⅱprotein/APLP2 may be a Go-coupled receptor involved in mediating the observed cell survival enhancing effect of MIS in sperm.
In the present study, base on previous study, we gained some further findings as follows: 1) MIS typeⅡreceptor (MISRII) mRNA is abundant in human and mouse testis but not in COS-7 cells, CHO cells and human sperm. These data implicated that COS-7 and CHO cells can be used as the cell model which provided the possibility of YWK-Ⅱprotein/APLP2 as a receptor mediating the effect of MIS in cell survival control. 2) In YWK-Ⅱ-overexpressing COS-7 cells, just like CHO cells, MIS activates the G_o-coupled ERK1/2 signaling pathway. These results provide further support for our previous conclusion, so, we presume, the YWK-Ⅱ-overexpressed CHO cells are appropriate for the purpose of this study. 3) In YWK-Ⅱ-overexpressing CHO cells, MIS promotes cell survival with altered levels of p53 and caspase-3. That is to say, MIS-enhanced cell viability was due to anti-apoptotic activity. On the other hand, we found YWK-Ⅱprotein/APLP2 is high expressed in pancreatic cancer by tissue chip. Further studies can be carried out to investigate the immunogenicity and possible application of YWK-Ⅱprotein/APLP2 in tumor immunotherapy.
Taken together, the present study has demonstrated a new G_o-coupled receptor for MIS in mediating ERK1/2 activation leading to anti-apoptotic activity or cell survival.
引文
Borodovsky, A., Kessler, B.M., Casagrande, R., Overkleeft, H.S., Wilkinson, K.D. and Ploegh, H.L. (2001) A novel active site-directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14. Embo J, 20, 5187-5196.
Brooks, P., Fuertes, G, Murray, R.Z., Bose, S., Knecht, E., Rechsteiner, M.C., Hendil, K.B., Tanaka, K., Dyson, J. and Rivett, J. (2000) Subcellular localization of proteasomes and their regulatory complexes in mammalian cells. Biochem J, 346 Pt 1, 155-161.
Cherix, N., Froquet, R., Charette, S.J., Blanc, C, Letourneur, F. and Cosson, P. (2006) A Phg2-Adrml pathway participates in the nutrient-controlled developmental response in Dictyostelium. Mol Biol Cell, 17,4982-4987.
Fujiki, Y., Hubbard, A.L., Fowler, S. and Lazarow, P.B. (1982) Isolation of intracellular membranes by means of sodium carbonate treatment: application to endoplasmic reticulum. J Cell Biol, 93,97-102.
Gandhi, T.K., Zhong, J., Mathivanan, S., Karthick, L., Chandrika, K.N., Mohan, S.S., Sharma, S., Pinkert, S., Nagaraju, S., Periaswamy, B., Mishra, G, Nandakumar, K., Shen, B., Deshpande, N., Nayak, R., Sarker, M., Boeke, J.D., Parmigiani, G., Schultz, J., Bader, J.S. and Pandey, A. (2006) Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat Genet, 38,285-293.
Glickman, M.H. and Ciechanover, A. (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev, 82, 373-428.
Goldberg, A.L. (2003) Protein degradation and protection against misfolded or damaged proteins. Nature, 426, 895-899.
Guerrero, C., Tagwerker, C, Kaiser, P. and Huang, L. (2006) An integrated mass spectrometry-based proteomic approach: quantitative analysis of tandem affinity-purified in vivo cross-linked protein complexes (QTAX) to decipher the 26 S proteasome-interacting network. Mol Cell Proteomics, 5, 366-378.
Guterman, A. and Glickman, M.H. (2004) Deubiquitinating enzymes are IN/(trinsic to proteasome function). Curr Protein Pept Sci, 5, 201 -211.
Hamazaki, J., Iemura, S., Natsume, T., Yashiroda, H., Tanaka, K. and Murata, S. (2006) A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. Embo J, 25, 4524-4536.
Hasegawa, K., Sakurai, N. and Kinoshita, T. (2001) Xoom is maternally stored and functions as a transmembrane protein for gastrulation movement in Xenopus embryos. Dev Growth Differ, 43,25-31.
Hershko, A. and Ciechanover, A. (1998) The ubiquitin system. Annu Rev Biochem, 67, 425-479.
Holzl, H., Kapelari, B., Kellermann, J., Seemuller, E., Sumegi, M., Udvardy, A., Medalia, O., Sperling, J., Muller, S.A., Engel, A. and Baumeister, W. (2000) The regulatory complex of Drosophila melanogaster 26S proteasomes. Subunit composition and localization of a deubiquitylating enzyme. J Cell Biol, 150, 119-130.
Horton, R.A., Strachan, E.A., Vogel, K.W. and Riddle, S.M. (2007) A substrate for deubiquitinating enzymes based on time-resolved fluorescence resonance energy transfer between terbium and yellow fluorescent protein. Anal Biochem, 360, 138-143.
Hough, R., Pratt, G. and Rechsteiner, M. (1987) Purification of two high molecular weight proteases from rabbit reticulocyte lysate. J Biol Chem, 262, 8303-8313.
Ito, T., Chiba, T., Ozawa, R., Yoshida, M., Hattori, M. and Sakaki, Y. (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci U S A, 98,4569-4574.
Jorgensen, J.P., Lauridsen, A.M., Kristensen, P., Dissing, K., Johnsen, A.H., Hendil, K.B. and Hartmann-Petersen, R. (2006) Adrml, a putative cell adhesion regulating protein, is a novel proteasome-associated factor. J Mol Biol, 360, 1043-1052.
Kolodziejski, P.J., Koo, J.S. and Eissa, N.T. (2004) Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors. Proc Natl Acad Sci U S A, 101, 18141-18146.
Lam, Y.A., DeMartino, GN., Pickart, CM. and Cohen, R.E. (1997a) Specificity of the ubiquitin isopeptidase in the PA700 regulatory complex of 26 S proteasomes. J Biol Chem, 272, 28438-28446.
Lam, Y.A., Xu, W., DeMartino, GN. and Cohen, R.E. (1997b) Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature, 385, 737-740.
Lamerant, N. and Kieda, C. (2005) Adhesion properties of adhesion-regulating molecule 1 protein on endothelial cells. FebsJ, 272, 1833-1844.
Leggett, D.S., Glickman, M.H. and Finley, D. (2005) Purification of proteasomes, proteasome subcomplexes, and proteasome-associated proteins from budding yeast. Methods Mol Biol, 301, 57-70.
Leggett, D.S., Hanna, J., Borodovsky, A., Crosas, B., Schmidt, M., Baker, R.T., Walz, T., Ploegh, H. and Finley, D. (2002) Multiple associated proteins regulate proteasome structure and function. Mol Cell, 10,495-507.
Li, T., Duan, W., Yang, H., Lee, M.K., Bte Mustafa, F., Lee, B.H. and Teo, T.S. (2001) Identification of two proteins, S14 and UIP1, that interact with UCH37. FEBS Lett, 488, 201-205.
Li, T., Naqvi, N.I., Yang, H. and Teo, T.S. (2000) Identification of a 26S proteasome-associated UCH in fission yeast. Biochem Biophys Res Commun, 272, 270-275.
Musial, A. and Eissa, N.T. (2001) Inducible nitric-oxide synthase is regulated by the proteasome degradation pathway. J Biol Chem, 276, 24268-24273.
Nakane, X, Inada, Y., Itoh, F. and Chiba, S. (2000) Rat homologue of the human M(r) 110000 antigen is the protein that expresses widely in various tissues. Biochim Biophys Acta, 1493,378-382.
Ovaa, H., Kessler, B.M., Rolen, U., Galardy, P.J., Ploegh, H.L. and Masucci, M.G (2004) Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Natl Acad Sci U S A, 101, 2253-2258.
Palmer, A., Rivett, A.J., Thomson, S., Hendil, K.B., Butcher, G.W., Fuertes, G. and Knecht, E. (1996) Subpopulations of proteasomes in rat liver nuclei, microsomes and cytosol. Biochem J, 316 ( Pt 2), 401-407.
Pickart, CM. and Cohen, R.E. (2004) Proteasomes and their kin: proteases in the machine age. Nat Rev Mol Cell Biol, 5, 177-187.
Pilarsky, C, Wenzig, M., Specht, T., Saeger, H.D. and Grutzmann, R. (2004) Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia, 6, 744-750.
Qiu, X.B., Ouyang, S.Y., Li, C.J., Miao, S., Wang, L. and Goldberg, A.L. (2006) hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. Embo J, 25, 5742-5753.
Ratovitski, E.A., Bao, C, Quick, R.A., McMillan, A., Kozlovsky, C. and Lowenstein, C.J. (1999) An inducible nitric-oxide synthase (NOS)-associated protein inhibits NOS dimerization and activity. J Biol Chem, 274, 30250-30257.
Realini, C, Rogers, S.W. and Rechsteiner, M. (1994) KEKE motifs. Proposed roles in protein-protein association and presentation of peptides by MHC class I receptors. FEBS Lett,348, 109-113.
Rock, K.L., York, I.A., Saric, T. and Goldberg, A.L. (2002) Protein degradation and the generation of MHC class I-presented peptides. Adv Immunol, 80, 1-70.
Rolen, U., Kobzeva, V., Gasparjan, N., Ovaa, H., Winberg, G, Kisseljov, F. and Masucci, M.G (2006) Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines. Mol Carcinog, 45, 260-269.
Seong, K.M., Baek, J.H., Yu, M.H. and Kim, J. (2007) Rpnl3p and Rpnl4p are involved in the recognition of ubiquitinated Gcn4p by the 26S proteasome. FEBS Lett. 2007 Apr 30; [Epub ahead of print]
Shimada, S., Ogawa, M., Schlom, J. and Greiner, J.W. (1991) Identification of a novel tumor-associated Mr 110,000 gene product in human gastric carcinoma cells that is immunologically related to carcinoembryonic antigen. Cancer Res, 51, 5694-5703.
Shimada, S., Ogawa, M., Takahashi, M., Schlom, J. and Greiner, J.W. (1994) Molecular cloning and characterization of the complementary DNA of an M(r) 110,000 antigen expressed by human gastric carcinoma cells and upregulated by gamma-interferon. Cancer Res, 54, 3831-3836.
Simins, A.B., Weighardt, H., Weidner, K.M., Weidle, U.H. and Holzmann, B. (1999) Functional cloning of ARM-1, an adhesion-regulating molecule upregulated in metastatic tumor cells. Clin Exp Metastasis, 17, 641-648.
Smith, D.M., Kafri, G., Cheng, Y, Ng, D., Walz, T. and Goldberg, A.L. (2005) ATP binding to PAN or the 26S ATPases causes association with the 20S proteasome, gate opening, and translocation of unfolded proteins. Mol Cell, 20, 687-698.
Sone, T., Saeki, Y, Toh-e, A. and Yokosawa, H. (2004) Sem1p is a novel subunit of the 26 S proteasome from Saccharomyces cerevisiae. J Biol Chem, 279, 28807-28816.
Stone, M., Hartmann-Petersen, R., Seeger, M., Bech-Otschir, D., Wallace, M. and Gordon, C. (2004) Uch2/Uch37 is the major deubiquitinating enzyme associated with the 26S proteasome in fission yeast. J Mol Biol, 344, 697-706.
Sumegi, M., Hunyadi-Gulyas, E., Medzihradszky, K.F. and Udvardy, A. (2003) 26S proteasome subunits are O-linked N-acetylglucosamine-modified in Drosophila melanogaster. Biochem Biophys Res Commun, 312, 1284-1289.
Verma, R., Aravind, L., Oania, R., McDonald, W.H., Yates, J.R., 3rd, Koonin, E.V. and Deshaies, R.J. (2002) Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science, 298, 611-615.
Verma, R., Chen, S., Feldman, R., Schieltz, D., Yates, J., Dohmen, J. and Deshaies, R.J. (2000) Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol Biol Cell, 11,3425-3439.
Voges, D., Zwickl, P. and Baumeister, W. (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem, 68, 1015-1068.
Wicks, S.J., Haros, K., Maillard, M, Song, L., Cohen, R.E., Dijke, P.T. and Chantry, A. (2005) The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling. Oncogene, 24, 8080-8084.
Winzeler, E.A., Shoemaker, D.D., Astromoff, A., Liang, H., Anderson, K., Andre, B., Bangham, R., Benito, R., Boeke, J.D., Bussey, H., Chu, A.M., Connelly, C, Davis, K., Dietrich, F., Dow, S.W., El Bakkoury, M., Foury, F., Friend, S.H., Gentalen, E., Giaever, G, Hegemann, J.H., Jones, T, Laub, M., Liao, H., Liebundguth, N., Lockhart, D.J., Lucau-Danila, A., Lussier, M., M'Rabet, N., Menard, P., Mittmann, M., Pai, C., Rebischung, C., Revuelta, J.L., Riles, L., Roberts, C.J., Ross-MacDonald, P., Scherens, B., Snyder, M, Sookhai-Mahadeo, S., Storms, R.K., Veronneau, S., Voet, M., Volckaert, G., Ward, T.R., Wysocki, R., Yen, GS., Yu, K., Zimmermann, K., Philippsen, P., Johnston, M. and Davis, R.W. (1999) Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science, 285, 901-906.
Wojcik, C. and DeMartino, GN. (2002) Analysis of Drosophila 26 S proteasome using RNA interference. J Biol Chem, 277, 6188-6197.
Yao, T. and Cohen, R.E. (2002) A cryptic protease couples deubiquitination and degradation by the proteasome. Nature, 419, 403-407.
Yao, T., Song, L., Xu, W., DeMartino, GN., Florens, L., Swanson, S.K., Washburn, M.P., Conaway, R.C., Conaway, J.W. and Cohen, R.E. (2006) Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrml. Nat Cell Biol, 8, 994-1002.
Araki, W. and Wurtman, R.J. (1998) Increased expression of amyloid precursor protein and amyloid precursor-like protein 2 during trophic factor withdrawal-induced death of neuronal PC12 cells. Brain Res Mol Brain Res, 56, 169-177.
Ariazi, E.A. and Gould, M.N. (1996) Identifying differential gene expression in monoterpene-treated mammary carcinomas using subtractive display. J Biol Chem, 271, 29286-29294.
Baarends, W.M., van Helmond, M.J., Post, M., van der Schoot, P.J., Hoogerbrugge, J.W., de Winter, J.P., Uilenbroek, J.T., Karels, B., Winning, L.G., Meijers, J.H. and et al. (1994) A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the mullerian duct. Development, 120, 189-197.
Bedecarrats, G.Y., O'Neill, F.H., Norwitz, E.R., Kaiser, U.B. and Teixeira, J. (2003) Regulation of gonadotropin gene expression by Mullerian inhibiting substance. Proc Natl Acad Sci U S A, 100,9348-9353.
Chang, E, Steelman, L.S., Shelton, J.G., Lee, J.T., Navolanic, P.M., Blalock, W.L., Franklin, R. and McCubrey, J.A. (2003) Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (Review). Int J Oncol, 22,469-480.
Fallat, M.E., Siow, Y., Klar, E.A., Belker, A.M. and MacLaughlin, D.T. (1998) The presence of Mullerian inhibiting substance binding sites in human sperm. J Urol, 159, 2210-2214.
Gouedard, L., Chen, Y.G, Thevenet, L., Racine, C, Borie, S., Lamarre, I., Josso, N., Massague, J. and di Clemente, N. (2000) Engagement of bone morphogenetic protein type IB receptor and Smadl signaling by anti-Mullerian hormone and its type II receptor. J Biol Chem, 275, 27973-27978.
Gudermann, T. (2001) Complexity in Biological Information Processing. John Wiley & Sons, Ltd., London, UK.
Gupta, V., Carey, J.L., Kawakubo, H., Muzikansky, A., Green, J.E., Donahoe, P.K., MacLaughlin, D.T. and Maheswaran, S. (2005) Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model. Proc Natl Acad Sci U S A, 102,3219-3224.
Haneji, T. and Koide, S.S. (1987) Identification of antigen in rat spermatogenic cells interacting with an anti-human sperm monoclonal antibody. Biol Reprod, 37,467-477.
Huang, P., Miao, S., Fan, H., Sheng, Q., Yan, Y., Wang, L. and Koide, S.S. (2000) Expression and characterization of the human YWK-II gene, encoding a sperm membrane protein related to the alzheimer betaA4-amyloid precursorprotein. Mol Hum Reprod, 6, 1069-1078.
Jarvis, W.D. and Grant, S. (1999) Protein kinase C targeting in antineoplastic treatment strategies. Invest New Drugs, 17, 227-240.
Kalejs, M. and Erenpreisa, J. (2005) Cancer/testis antigens and gametogenesis: a review and "brain-storming" session. Cancer Cell Int, 5, 4.
Lowe, S.W., Schmitt, E.M., Smith, S.W, Osborne, B.A. and Jacks, T. (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature, 362, 847-849.
Porter, A.G. and Janicke, R.U. (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ, 6,99-104.
Renaud, E.J., MacLaughlin, D.T, Oliva, E., Rueda, B.R. and Donahoe, P.K. (2005) Endometrial cancer is a receptor-mediated target for Mullerian Inhibiting Substance. Proc Natl Acad Sci U SA , 102,111-116.
Salhi, I., Cambon-Roques, S., Lamarre, I., Laune, D., Molina, E, Pugniere, M., Pourquier, D., Gutowski, M., Picard, J.Y., Xavier, F., Pelegrin, A. and Navarro-Teulon, I. (2004) The anti-Mullerian hormone type II receptor: insights into the binding domains recognized by a monoclonal antibody and the natural ligand. Biochem J, 379, 785-793.
Sandbrink, R., Masters, C.L. and Beyreuther, K. (1994) Complete nucleotide and deduced amino acid sequence of rat amyloid protein precursor-like protein 2 (APLP2/APPH): two amino acids length difference to human and murine homologues. Biochim Biophys Acta, 1219, 167-170.
Scanlan, M.J., Gure, A.O., Jungbluth, A.A., Old, L.J. and Chen, Y.T. (2002) Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev, 188, 22-32.
Sprecher, C.A., Grant, F.J., Grimm, G, O'Hara, P.J., Norris, F., Norris, K. and Foster, D.C. (1993) Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for a multigene family. Biochemistry, 32,4481-4486.
Teixeira, J. and Donahoe, P.K. (1996) Molecular biology of MIS and its receptors. J Androl, 17, 336-341.
Teixeira, J., Maheswaran, S. and Donahoe, P.K. (2001) Mullerian inhibiting substance: an instructive developmental hormone with diagnostic and possible therapeutic applications. Endocr Rev, 22, 657-674.
Tian, X.Y., Sha, Y.S., Zhang, S.M., Chen, Y.B., Miao, S.Y., Wang, L.F. and Koide, S.S. (2001) Extracellular domain of YWK-II, a human sperm transmembrane protein, interacts with rat Mullerian-inhibiting substance. Reproduction, 121, 873-880.
Vanage, G., Lu, Y.A., Tam, J.P. and Koide, S.S. (1992) Infertility induced in rats by immunization with synthetic peptide segments of a sperm protein. Biochem Biophys Res Commun, 183, 538-543.
Vanhauwe, J.F., Thomas, T.O., Minshall, R.D., Tiruppathi, C., Li, A., Gilchrist, A., Yoon, E.J., Malik, A.B. and Hamm, H.E. (2002) Thrombin receptors activate G(o) proteins in endothelial cells to regulate inrracellular calcium and cell shape changes. J Biol Chem, 277,34143-34149.
Visser, J.A., Olaso, R., Verhoef-Post, M., Kramer, P., Themmen, A.P. and Ingraham, H.A. (2001) The serine/threonine transmembrane receptor ALK2 mediates Mullerian inhibiting substance signaling. Mol Endocrinol, 15, 936-945.
von Koch, C.S., Zheng, H., Chen, H., Trumbauer, M., Thinakaran, G, van der Ploeg, L.H., Price, D.L. and Sisodia, S.S. (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging, 18, 661-669.
Wang, P.Y., Koishi, K., McGeachie, A.B., Kimber, M., Maclaughlin, D.T., Donahoe, P.K. and McLennan, I.S. (2005) Mullerian inhibiting substance acts as a motor neuron survival factor in vitro. Proc Natl Acad Sci U S A, 102, 16421-16425.
Werry, T.D., Sexton, P.M. and Christopoulos, A. (2005) "Ins and outs" of seven-transmembrane receptor signalling to ERK. Trends Endocrinol Metab, 16, 26-33.
Yan, Y.C., Bai, Y., Wang, L.F., Miao, S.Y. and Koide, S.S. (1990) Characterization of cDNA encoding a human sperm membrane protein related to A4 amyloid protein. Proc Natl Acad Sci U S A, 87, 2405-2408.
Yan, Y.C., Wang, L.F., Mitsudo, S.M. and Koide, S.S. (1986) Characterization of an antisperm monoclonal antibody inducing human sperm agglutination. Immunological Approch to Contraception and Promotion of Fertility. G P. Talwar, New York, pp. 231-240.
Zhuang, D., Qiao, Y., Zhang, X., Miao, S., Koide, S.S. and Wang, L. (2006a) YWK-II protein/APLP2 in mouse gametes: potential role in fertilization. Mol Reprod Dev, 73, 61-67.
Zhuang, D., Wang, Y., Yang, C., Qiao, Y., Miao, S., Koide, S.S. and Wang, L. (2006b) Delineation of the functional domains of the extracellular region of YWK-II Protein/APLP2 of sperm membrane. Front Biosci, 11, 2371-2380.
Cherix, N., Froquet, R., Charette, S.J., Blanc, C., Letourneur, F. and Cosson, P. (2006) A Phg2-Adrml pathway participates in the nutrient-controlled developmental response in Dictyostelium. Mol Biol Cell, 17, 4982-4987.
Gavin, A.C., Aloy, P., Grandi, P., Krause, R., Boesche, M., Marzioch, M., Rau, C, Jensen, L.J., Bastuck, S., Dumpelfeld, B., Edelmann, A., Heurtier, M.A., Hoffman, V., Hoefert, C, Klein, K., Hudak, M., Michon, A.M., Schelder, M., Schirle, M., Remor, M., Rudi, T., Hooper, S., Bauer, A., Bouwmeester, T., Casari, G., Drewes, G., Neubauer, G., Rick, J.M., Kuster, B., Bork, P., Russell, R.B. and Superti-Furga, G (2006) Proteome survey reveals modularity of the yeast cell machinery. Nature, 440, 631-636.
Gavin, A.C., Bosche, M., Krause, R., Grandi, P., Marzioch, M., Bauer, A., Schultz, J., Rick, J.M., Michon, A.M., Cruciat, C.M., Remor, M., Hofert, C., Schelder, M., Brajenovic, M., Ruffner, H., Merino, A., Klein, K., Hudak, M., Dickson, D., Rudi, T., Gnau, V., Bauch, A., Bastuck, S., Huhse, B., Leutwein, C, Heurtier, M.A., Copley, R.R., Edelmann, A., Querfurth, E., Rybin, V., Drewes, G., Raida, M., Bouwmeester, T., Bork, P., Seraphin, B., Kuster, B., Neubauer, G and Superti-Furga, G (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature, 415, 141-147.
Hamazaki, J., Iemura, S., Natsume, T., Yashiroda, H., Tanaka, K. and Murata, S. (2006) A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. Embo J, 25, 4524-4536.
Ito, T., Chiba, T., Ozawa, R., Yoshida, M., Hattori, M. and Sakaki, Y. (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci U S A, 98, 4569-4574.
Jorgensen, J.P., Lauridsen, A.M., Kristensen, P., Dissing, K., Johnsen, A.H., Hendil, K.B. and Hartmann-Petersen, R. (2006) Adrm 1, a putative cell adhesion regulating protein, is a novel proteasome-associated factor. J Mol Biol, 360, 1043-1052.
Kolodziejski, P.J., Koo, J.S. and Eissa, N.T. (2004) Regulation of inducible nitric oxide synthase by rapid cellular turnover and cotranslational down-regulation by dimerization inhibitors. Proc Natl Acad Sci U S A, 101, 18141-18146.
Krogan, N.J., Cagney, G., Yu, H., Zhong, G., Guo, X., Ignatchenko, A., Li, J., Pu, S., Datta, N., Tikuisis, A.P., Punna, T., Peregrin-Alvarez, J.M., Shales, M., Zhang, X., Davey, M., Robinson, M.D., Paccanaro, A., Bray, J.E., Sheung, A., Beattie, B., Richards, D.P., Canadien, V., Lalev, A., Mena, F., Wong, P., Starostine, A., Canete, M.M., Vlasblom, J., Wu, S., Orsi, C., Collins, S.R., Chandran, S., Haw, R., Rilstone, J.J., Gandi, K., Thompson, N.J., Musso, G., St Onge, P., Ghanny, S., Lam, M.H., Butland, G., Altaf-Ul, A.M., Kanaya, S., Shilatifard, A., O'Shea, E., Weissman, J.S., Ingles, C.J., Hughes, T.R., Parkinson, J., Gerstein, M., Wodak, S.J., Emili, A. and Greenblatt, J.F. (2006) Global landscape of protein complexes in the yeast Saccharomyces cerevisiae. Nature, 440, 637-643.
Lamerant, N. and Kieda, C. (2005) Adhesion properties of adhesion-regulating molecule 1 protein on endothelial cells. Febs J, 272, 1833-1844.
Musial, A. and Eissa, N.T. (2001) Inducible nitric-oxide synthase is regulated by the proteasome degradation pathway. J Biol Chem, 276, 24268-24273.
Nakane, T., Inada, Y., Itoh, F. and Chiba, S. (2000) Rat homologue of the human M(r) 110000 antigen is the protein that expresses widely in various tissues. Biochim Biophys Acta, 1493, 378-382.
Pan, X., Ye, P., Yuan, D.S., Wang, X., Bader, J.S. and Boeke, J.D. (2006) A DNA integrity network in the yeast Saccharomyces cerevisiae. Cell, 124, 1069-1081.
Pilarsky, C., Wenzig, M., Specht, T., Saeger, H.D. and Grutzmann, R. (2004) Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia, 6, 744-750.
Qiu, X.B., Ouyang, S.Y, Li, C.J., Miao, S., Wang, L. and Goldberg, A.L. (2006) hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. Embo J, 25, 5742-5753.
Ratovitski, E.A., Bao, C, Quick, R.A., McMillan, A., Kozlovsky, C. and Lowenstein, C.J. (1999) An inducible nitric-oxide synthase (NOS)-associated protein inhibits NOS dimerization and activity. J Biol Chem, 274, 30250-30257.
Seong, K.M., Baek, J.H., Yu, M.H. and Kim, J. (2007) Rpnl3p and Rpn14p are involved in the recognition of ubiquitinated Gcn4p by the 26S proteasome. FEBS Lett. 2007 Apr 30; [Epub ahead of print]
Shimada, S., Ogawa, M., Schlom, J. and Greiner, J.W. (1991) Identification of a novel tumor-associated Mr 110,000 gene product in human gastric carcinoma cells that is immunologically related to carcinoembryonic antigen. Cancer Res, 51, 5694-5703.
Shimada, S., Ogawa, M., Takahashi, M., Schlom, J. and Greiner, J.W. (1994) Molecular cloning and characterization of the complementary DNA of an M(r) 110,000 antigen expressed by human gastric carcinoma cells and upregulated by gamma-interferon. Cancer Res, 54, 3831-3836.
Simins, A.B., Weighardt, H., Weidner, K.M., Weidle, U.H. and Holzmann, B. (1999) Functional cloning of ARM-1, an adhesion-regulating molecule upregulated in metastatic tumor cells. Clin Exp Metastasis, 17, 641-648.
Sone, T., Saeki, Y., Toh-e, A. and Yokosawa, H. (2004) Sem1p is a novel subunit of the 26 S proteasome from Saccharomyces cerevisiae. J Biol Chem, 279, 28807-28816.
Sumegi, M., Hunyadi-Gulyas, E., Medzihradszky, K.F. and Udvardy, A. (2003) 26S proteasome subunits are O-linked N-acetylglucosamine-modified in Drosophila melanogaster. Biochem Biophys Res Commun, 312, 1284-1289.
Verma, R., Chen, S., Feldman, R., Schieltz, D., Yates, J., Dohmen, J. and Deshaies, R.J. (2000) Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol Biol Cell, 11, 3425-3439.
Yao, T., Song, L., Xu, W., DeMartino, G.N., Florens, L., Swanson, S.K., Washburn, M.P., Conaway, R.C., Conaway, J.W. and Cohen, R.E. (2006) Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm 1. Nat Cell Biol, 8, 994-1002.
