What we know about ST13, a co-factor of heat shock protein, or a tumor suppressor?

What we know about ST13, a co-factor of heat shock protein, or a tumor suppressor? first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:zhengshu@zju.edu.cn †E-mail:zhengshu@zju.edu.cn zhengshu@zju.edu.cn The Second Affiliated Hospital, Cancer Institute, School of Medicine, Zhejiang University, Hangzhou 310009, China The Second Affiliated Hospital, Cancer Institute, School of Medicine, Zhejiang University, Hangzhou 310009, China This article is to summarize the molecular and functional analysis of the gene “suppression of tumorigenicity 13” (ST13). ST13 is in fact the gene encoding Hsp70 interacting protein (Hip), a co-factor (co-chaperone) of the 70-kDa heat shock proteins (Hsc/Hsp70). By collaborating with other positive co-factors such as Hsp40 and the Hsp70-Hsp90 organizing protein (Hop), or competing with negative co-factors such as Bcl2-associated athanogen 1 (Bag1), Hip may facilitate the chaperone function of Hsc/Hsp70 in protein folding and repair, and in controlling the activity of regulatory proteins such as steroid receptors and regulators of proliferation or apoptosis. Although the nomenclature of ST13 implies a role in the suppression of tumorigenicity (ST), to date available experimental data are not sufficient to support its role in cancer development, except for the possible down-regulation of ST13 in gastric and colorectal cancers. Further investigation of this gene at the physiological level would benefit our understanding of diseases such as endocrinological disorders, cancer, and neurodegeneration commonly associated with protein misfolding. ST13 Hip p48 Hsc/Hsp70 Heat shock protein Protein folding Steroid receptor Tumorigenicity INTRODUCTION 1 In the early 1990’s, in an attempt to clone differentially expressed genes in human colorectal cancer, scientists at Zhejiang Medical University (now School of Medicine, Zhejiang University) and Shanghai Cancer Institution implemented a cDNA technology called “subtractive hybridization” (Shi et al., 1992 1992 ; Zheng et al., 1994 1994 ; 1997 1997 ; Mo et al., 1996 1996 ; Cao et al., 1997 1997 ). As a result, 46 cDNA clones were isolated and their corresponding genes were identified as “down-regulated” genes in colorectal cancers. These clones were initially named as an “SNC” series (subtracted from normal and cancer tissues), and two of them, SNC6 and SNC19, were deposited at GenBank with full-length cDNA sequences by Zheng et al.( 1994 1994 ). SNC6 was then annotated as the “human putative tumor suppressor SNC6” with accession No. U17714. Historically this was the first record of this human gene in public databases. In recent versions of GenBank, U17714 has been replaced by NM_003932 and renamed as “suppression of tumorigenicity 13 (ST13) (colon carcinoma) (Hsp70 interacting protein)”. What is ST13 and its function? Is there any implication of this gene in human disease? This paper presents a review on gene ST13, addressing these questions with the information to date available from public databases and literature. DATA MINING 1 As an official gene symbol approved by HUGO (Human Genome Organization), “ST13” is currently accessible at multiple public databases, e.g., Entrez Gene: 6767, UniGene: Hs.447477, HGNC (HUGO Gene Nomenclature Committee): 11343, OMIM (Online Mendelian Inheritance in Man): 606796, and HPRD (Human Protein Reference Database): 08426. According to these data, ST13, mapped on chromosome 22q13, encodes a 369-amino acid, cytosolic protein. ST13 contains a TPR (tetratricopeptide repeat) domain at its central region and a Sti1 domain (heat shock chaperonin-binding motif) at its C-terminus (Fig. 1a 1a ). However, there is considerable confusion in the nomenclature of this gene. Besides ST13 and SNC6, it has also designated as Hip (Hsp70 interacting protein), p48 (progesterone receptor-associated p48 protein), or Hop (Hsp70-Hsp90 organizing protein). Databases such as Entrez Gene and OMIM summarize the gene with biographies originally for Hop or for both Hip and Hop. After careful data curation, we identified that Hip and p48 are indeed the same protein, and the correct gene product of ST13. However, Hop, a protein of 543 residues containing 3 TPR domains and one C-terminal Sti1 domain, is encoded by the gene STIP1 (stress-induced-phosphoprotein 1) located on chromosome 11q13. Obviously, Hop has been misplaced and this particular entry calls for database revision. This article accordingly refers to Hip or p48 as the protein product of the ST13 gene. Cloning 2 Hip first appeared in the literature as the 48-kDa component, p48, of progesterone receptor (PR)-chaperone complexes found in rabbit reticulocyte lysates (Smith, 1993 1993 ; Smith et al., 1995 1995 ). Using an antibody developed against the purified rabbit p48 protein, Prapapanich et al.( 1996a 1996a ) cloned human p48 cDNA from a HeLa cell cDNA library. The deduced 369-amino acid protein had a calculated molecular mass of ~41 kDa. However, the protein product from the cDNA migrated identically with rabbit p48 by SDS-PAGE and associated with PR in a similar manner (Prapapanich et al., 1996a 1996a ). Independently, around the same time or a little earlier, the cloning of Hip was also accomplished by another two groups: Zheng et al.( 1994 1994 ), in the above-described search for genes differentially expressed in colorectal cancer, and Höhfeld et al.( 1995 1995 ), in a search for proteins interacting with the 70-kDa heat shock proteins (Hsc/Hsp70). In the latter case, the N-terminal ATPase domain of Hsc70 was used as bait in yeast two-hybrid screening of a rat cDNA library. A cDNA sequence encoding a 41-kDa protein was isolated and designated Hip. Given that the human p48 cDNA and the rat Hip cDNA are over 90% identical, and that they are the presumptive species homologues of each other, in most subsequent publications, including that from Prapapanich et al.( 1996a 1996a ), the term Hip has been adopted in place of p48. Protein structure 2 In the same report of Hip cloning, Höhfeld et al.( 1995 1995 ) demonstrated that Hip regulates Hsc70 activity. Hip binds to the Hsc70 ATPase domain and stabilizes the chaperone in the ADP-bound form having high affinity for polypeptide substrates (see below for details). In order to better understand the function of this novel co-chaperone, structural elements of the protein were characterized based on sequence alignment criteria and mutagenesis studies (Prapapanich et al., 1996b 1996b ; 1998 1998 ; Irmer and Höhfeld, 1997 1997 ). As shown in Fig. 1a 1a , Hip is composed of an N-terminal region (residues 1~100), a central, TPR domain (residues 114~215) followed by a highly charged region (residues 230~272), and a C-terminal region (residues 283~369) containing GGMP repeats and a Sti1 motif. Analysis of various Hip mutants encoded by truncated or deleted cDNAs revealed that the Hip TPR domain and flanking highly charged region are required for Hip to bind the Hsc/Hsp70 ATPase domain. The TPR is a protein-protein interaction domain which particularly facilitates interaction with heat shock proteins. The TPR domain had been previously found in Hop and in the Hsp90-binding immunophilins. The N-terminal region is responsible for protein homo-oligomerization, likely dimerization (Velten et al., 2000 2000 ; 2002 2002 ). However, monomeric Hip is still able to bind Hsp70, suggesting that homo-oligomerization is not required for interaction with Hsp70 (Prapapanich et al., 1996b 1996b ). Another publication reported that truncating the N-terminus demolished Hip’s ability to stimulate Hsp70-mediated protein refolding (Nollen et al., 2001 2001 ). As for the C-terminal region, within which the GGMP repeats and the Sti1 motif are known to be shared by Hsp70 and Hop, respectively, the exact function remains unclear. Prapapanich et al.( 1998 1998 ) suggested that the C-terminal region of Hip may function in Hsc70-Hsp90 cooperation. Molecular function 2 Since Hip was first identified through its interaction with the ATP-binding domain of Hsc70, and found to share structural domains with Hsc70 and other Hsc70/Hsp90-asssociated co-chaperones, it has long been considered as an Hsp70-specific co-chaperone. The mammalian cytosolic Hsp70 proteins (or Hsc/Hsp70, referring to both the constitutively expressed 70 kDa heat shock cognate protein Hsc70 and the heat-inducible Hsp70) are key chaperones in protein folding, assembly, transport, degradation, and control of the activity of regulatory proteins (e.g., steroid hormone receptors, certain kinases and transcription factors) (Hartl, 1996 1996 ; Bukau and Horwich, 1998 1998 ; Esser et al., 2004 2004 ; Mayer and Bukau, 2005 2005 ). Hsc/Hsp70 appears to function in a dynamic cycle of binding and releasing polypeptide substrate coupled to a cycle of ATP binding and hydrolysis by the intramolecular ATPase. In the ATP-bound state, Hsc/Hsp70 exhibits fast kinetics and low affinity for polypeptide substrates, whereas in the ADP-bound state, Hsc/Hsp70 exhibits slow kinetics and high affinity for polypeptide substrates. Current models of how these cycling states are regulated involve at least five different co-chaperones: Hsp40, Hip, Hop, Bag-1 (Bcl2-associated athanogene 1, or RAP46), and CHIP (carboxy terminus of Hsc70 interacting protein) (Figs. 1b 1b ). As shown in Fig. 1b 1b , the initial binding of Hsc/Hsp70 to a polypeptide substrate is achieved through cooperation of the chaperone with a member of the Hsp40 family, homologues of the bacterial DnaJ protein (Freeman et al., 1995 1995 ). Hsp40 stimulates the ATPase activity of Hsc/Hsp70 and generates the high affinity, ADP-bound state. However, in the presence of Hsp40 alone, the ADP state of Hsc/Hsp70 is unstable, and the newly formed Hsc/Hsp70-sub-strate complex may end up with premature dissociation (Höhfeld et al., 1995 1995 ). As described above, the TPR domain of Hip binds to the Hsc70 ATPase domain; this stabilizes the ADP-bound state of Hsc/Hsp70, thus stabilizing the chaperone-substrate complex (Höhfeld et al., 1995 1995 ). Subsequently, another co-chaperone Hop, homologue of yeast Sti1, associates with Hsp70: the Hop TPR domain binds to the Hsp70 C-terminus. Hop is actually an Hsp70/Hsp90-organization protein (as it is named), with its three TPR domains serving as non-overlapping binding sites for both Hsp70 and Hsp90. Interaction with Hop directs Hsp90 to the Hsp70 substrate complex (Frydman and Höhfeld, 1997 1997 ; Chen and Smith, 1998 1998 ; Hernandez et al., 2002 2002 ). As Hop can stimulate ADP/ATP exchange by Hsp70, Hop’s coupling of Hsp70 and Hsp90 is accompanied by transfer of substrate from Hsp70 to Hsp90, and release Hsp70 chaperone components. This Hsp70-Hsp90 cooperation is considered necessary for the conformational regulation of signaling proteins such as tyrosine kinases and steroid hormone receptors (Frydman and Höhfeld, 1997 1997 ). In addition to these positive regulators of the Hsp70 chaperone, two inhibitory co-chaperones have been identified: Bag-1 and CHIP. Bag-1 was originally discovered as a Bcl2-associated protein. Bag-1 has since been found to bind the ATPase domain of Hsp70 in a manner competitive with Hip (Höhfeld and Jentsch, 1997 1997 ; Takayama et al., 1999 1999 ; Alberti et al., 2003 2003 ). In contrast to Hip, Bag-1 stimulates the ADP dissociation rate of Hsc/Hsp70, promoting the release of polypeptide substrates, and thus inhibiting Hsc/Hsp70 chaperone activity. Several Bag-1-related proteins have recently been identified in human cells (Takayama et al., 1999 1999 ). They all share a conserved BAG domain and compete with Hip in binding to the ATPase domain of Hsc/Hsp70 in vitro. Bag-1 also contains an ubiquitin-like domain that is anticipated to mediate the interaction of Bag-1 with the proteasome (Alberti et al., 2002 2002 ). CHIP initially identified as a negative co-factor for human Hsc70, has both a TPR domain and an ubiquitin ligase-related U-box domain (Ballinger et al., 1999 1999 ; Murata et al., 2001 2001 ; 2003 2003 ). The CHIP TPR domain competes with Hop for binding to Hsc70 and Hsp90, and inhibits Hsp40-stimulated Hsc/Hsp70 ATPase activity. Meanwhile the CHIP U-box domain acts as an E3-ubiquitin ligase to promote the ubiquitination and proteasomal degradation of the Hsc/Hsp70 polypeptide substrates (Murata et al., 2001 2001 ; 2003 2003 ). Thus, both inhibitory co-factors Bag-1 and CHIP have the potential to shift Hsp70 activity from protein folding to protein degradation. In summary, the chaperone activity of Hsc/Hsp70 is regulated by a network of cooperating and competing co-factors; among these, the ST13 gene product Hip is one of the major positive regulators stabilizing the ADP state of Hsc/Hsp70 and thereby preventing premature release and/or proteolysis of substrate. Despite considerable progress in understanding the general mode of interaction between Hsc/Hsp70 and these co-chaperones, the exact molecular mechanism by which an individual cofactor, such as Hip, acts toward a specific substrate, such as steroid receptors, is still unclear and somewhat controversial. A model has been proposed in which Hip mediates the transition of PR complexes from early to intermediate stages; this model is based on the observation that C-terminal dominant-negative mutants of Hip cause a dose-dependent inhibition of receptor assembly with Hsp90 (Prapapanich et al., 1998 1998 ). However, other studies suggest that Hip is not essential for the in vitro assembly of the multi-chaperone complexes for either PR or the glucocorticoid receptor (GR) (Kosano et al., 1998 1998 ; Kanelakis et al., 2000 2000 ). Depletion of Hip from the in vitro system or addition of high levels of Hip does not affect the rate of receptor assembly and functional maturation (Kanelakis et al., 2000 2000 ). The same set of data revealed an alternative role for Hip in the regulation of GR signaling. Hip can oppose the inhibition Bag-1 exerts on receptor assembly and activation. In contrast, a more recent report maintains that the functional maturation of GR is directly enhanced by Hip (Nelson et al., 2004 2004 ). It has also been questioned if Hip does stabilize Hsp70 binding to GR (Kanelakis et al., 2000 2000 ), and if binding of Hip to Hsp70 is required for Hip’s effect on GR maturation (Nelson et al., 2004 2004 ). Furthermore, new evidence indicates that Hip can directly interact with certain protein substrates (e.g., the membrane chemokine receptor CXCR2) in an Hsp70-independent manner (Fan et al., 2002 2002 ). Physiological and pathophysiological role 2 To date, most of our knowledge regarding Hip has been obtained at the molecular level. Very little is known about the function of Hip in vivo. No human hereditary disease has been linked to the gene ST13 (see OMIM link 606796). Neither in vivo transgenic nor knockout studies on this gene have been reported. Based on Hip’s function as a positive co-factor for Hsp70, one can speculate that Hip plays a physiological role similar to or overlapping with that of Hsp70. Protein misfolding and aggregation are considered major contributors to neurodegenerative disorders such as Alzheimer’s, Huntington’s or prion disease. Hsp70 is expected to provide a means of treating these diseases due to the association of Hsp70 with aggregated or misfolded proteins with Hsp70 (Barral et al., 2004 2004 ). Induction of Hsp70 has shown signs of help in neurological diseases and other chronic conditions (Klettner, 2004 2004 ; Mayer and Bukau, 2005 2005 ; Sõti et al., 2005 2005 ; Evans et al., 2006 2006 ). However, no experimental evidence has yet linked Hip with these diseases, nor has even an expressional correlation been shown. Another well-recognized function of Hsp70 is the conformational regulation of signal transduction proteins. These proteins, called clients, include nuclear receptors such as PR and GR, kinases such as Raf, eIF2α-kinase, or CyclinB1/Cdk1, and transcription factors such as HSF, c-Myc, or pRb. As mentioned, Hip itself is a component of the PR assembly complex (Smith, 1993 1993 ; Smith et al., 1995 1995 ; Prapapanich et al., 1996a 1996a ), and may enhance the functional maturation of GR in vitro (Nelson et al., 2004 2004 ). However, data has not confirmed that Hip actually plays a role in the endocrine system in vivo. It is hypothesized that the expression levels of chaperones and co-chaperones might be determinants of glucocorticoid resistance in the treatment of acute lymphoblastic leukemia (ALL). Apparently this is not the case, since Tissing et al.( 2005 2005 ) found no significant difference in the mRNA levels of these (co)chaperones, including Hip, between glucocorticoid-sensitive and -resistant patients. On the other hand, much more attention has been paid to the implication of Hsp70 in cancer and cancer therapy. This research focus derives from the following points: (1) Hsp70 has been expected to function in signal transduction, cell cycle regulation, differentiation, and programmed cell death through interacting with its client proteins; (2) over-expression of Hsp70 leads to increased resistance to apoptotic agents (Jäättelä et al., 1998 1998 ; Jäättelä, 1999 1999 ), whereas selective depletion of Hsp70 results in massive apoptosis of cancer cells (Nylandsted et al., 2000 2000 ); (3) Hsp70 is generally expressed in various human tumors and tumor cell lines, with the level of expression correlating with poor therapeutic outcome in certain cancers (e.g., breast, endometrial, uterine cervical, and bladder carcinomas) (Ciocca and Calderwood, 2005 2005 ; Ciocca et al., 1993 1993 ; Vargas-Roig et al., 1997 1997 ); and (4) inhibitors of Hsp70’s sister chaperone Hsp90, such as 17-AAG, exhibit a broad spectrum of anti-tumor activity and appear promising in clinical trails (Sõti et al., 2005 2005 ; Neckers and Neckers, 2005 2005 ). But no role in cancer has yet been defined for the chaperone co-factor Hip. So far only a few expression studies have been published, mostly from Zheng Shu’s group who originally cloned the ST13 gene. Using Northern blot analysis and quantitative RT-PCR approaches, a decreased level of ST13 mRNA was observed in multiple colorectal cancer samples relative to that in their adjacent normal mucosa (Mo et al., 1996 1996 ; 1997a 1997a ; 1997b 1997b ; Li and Zhang, 2000 2000 ). However, the levels of ST13 mRNA showed no significant correlation with a tumor’s differentiation grade, Dukes’ stage, invasion depth, lymph node metastasis, or disease-specific survival (Dong et al., 2005 2005 ). Similarly, recent in situ hybridization found that only 3 of 7 colon cancer tissues analyzed were positive for ST13 mRNA, whereas 7 of 7 normal colon tissues were positive (Wang et al., 2005 2005 ). Nevertheless, caution should be taken in the annotation of ST13 as a gene down-regulated in human cancer. It is necessary to examine gene expression at the protein level as well. In addition, patterns of Hip protein expression among different cancer tissues, and correlation between the protein level and the morphological grade for individual cancers, should also be addressed. If Hip protein expression patterns mimic the data so far obtained at the RNA level, it would spur investigation as to why this Hsp70 cochaperone is down-regulated while the chaperone itself is over-expressed (see above). A recently reported immunohistochemistry study indicated that this down-regulation of Hip protein was likely a special case for gastric and colorectal carcinomas (Zheng et al., 2005 2005 ). Other types of cancers examined in the same study failed to follow this pattern. In contrast, as compared with their adjacent normal tissues, carcinomas of breast, ovary, and endometrium all exhibited increased signal intensity when probed with the anti-Hip antibody (Zheng et al., 2005 2005 ). SUMMARY 1 The name of gene ST13 implies a correlation with certain aspects of tumorigenicity. However, so far there is no adequate experimental data to support this, except for the possible decrease in gene expression in merely gastric and colorectal carcinomas. A considerable gap exists between describing this gene as down-regulated in tumors and describing it as a suppressor of tumorigenesis, unless a functional connection or pertinent mutations are found for this gene. The chromosomal region to which ST13 mapped, 22q13 (Zhang et al., 1998 1998 ), has shown frequent loss of heterozygosity in colorectal, breast, and ovarian carcinomas (Castells et al., 2000 2000 ). However, according to a detailed human chromosome map (the Human Genome Project), location of ST13 (22q13.2) is apparently outside the minimal region of deletion that is common for both breast and colorectal cancers (Castells et al., 2000 2000 ). It would be worthwhile to empirically determine whether ST13 is subject to loss of heterozygosity in these carcinomas. At the molecular level, ST13 is confirmed to be the gene encoding Hip, a positive co-factor of Hsc/Hsp70. Hip may facilitate the chaperone function of Hsc/Hsp70 in protein folding and in controlling the activity of regulatory proteins such as steroid receptors and regulators of proliferation or apoptosis. We recommend future investigation at the physiological level to address its implication in diseases: in protein misfolding-associated neurodegeneration, in endocrinological disorders, and in cancer. References S Alberti , J Demand , C Esser , N Emmerich , H Schild , J Höhfeld . Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome . J Biol Chem , 2002 . 277 ( 48 ): 45920 - 45927 . 12297498 DOI: 10.1074/jbc.M204196200 http://doi.org/10.1074/jbc.M204196200 . Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome S Alberti , C Esser , J Höhfeld . BAG-1–a nucleotide exchange factor of Hsc70 with multiple cellular functions . Cell Stress Chaperones , 2003 . 8 ( 3 ): 225 - 231 . 14984055 DOI: 10.1379/1466-1268(2003)008<0225:BNEFOH>2.0.CO;2 http://doi.org/10.1379/1466-1268(2003)008<0225:BNEFOH>2.0.CO;2 . BAG-1–a nucleotide exchange factor of Hsc70 with multiple cellular functions CA Ballinger , P Connell , Y Wu , Z Hu , LJ Thompson , LY Yin , C Patterson . Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions . Mol Cell Biol , 1999 . 19 ( 6 ): 4535 - 4545 . 10330192 . Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions JM Barral , SA Broadley , G Schaffar , FU Hartl . Roles of molecular chaperones in protein misfolding diseases . Semin Cell Dev Biol , 2004 . 15 ( 1 ): 17 - 29 . 15036203 DOI: 10.1016/j.semcdb.2003.12.010 http://doi.org/10.1016/j.semcdb.2003.12.010 . Roles of molecular chaperones in protein misfolding diseases B Bukau , AL Horwich . The Hsp70 and Hsp60 chaperone machines . Cell , 1998 . 92 ( 3 ): 351 - 366 . 9476895 DOI: 10.1016/S0092-8674(00)80928-9 http://doi.org/10.1016/S0092-8674(00)80928-9 . The Hsp70 and Hsp60 chaperone machines J Cao , X Cai , L Zheng , L Geng , Z Shi , CC Pao , S Zheng . Characterization of colorectal-cancer-related cDNA clones obtained by subtractive hybridization screening . J Cancer Res Clin Oncol , 1997 . 123 ( 8 ): 447 - 451 . 9292708 DOI: 10.1007/s004320050085 http://doi.org/10.1007/s004320050085 . Characterization of colorectal-cancer-related cDNA clones obtained by subtractive hybridization screening A Castells , JF Gusella , V Ramesh , AK Rustgi . A region of deletion on chromosome 22q13 is common to human breast and colorectal cancers . Cancer Res , 2000 . 60 ( 11 ): 2836 - 2839 . 10850424 . A region of deletion on chromosome 22q13 is common to human breast and colorectal cancers S Chen , DF Smith . Hop as an adaptor in the heat shock protein 70 (Hsp70) and Hsp90 chaperone machinery . J Biol Chem , 1998 . 273 ( 52 ): 35194 - 35200 . 9857057 DOI: 10.1074/jbc.273.52.35194 http://doi.org/10.1074/jbc.273.52.35194 . Hop as an adaptor in the heat shock protein 70 (Hsp70) and Hsp90 chaperone machinery DR Ciocca , SK Calderwood . Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications . Cell Stress Chaperones , 2005 . 10 ( 2 ): 86 - 103 . 16038406 DOI: 10.1379/CSC-99r.1 http://doi.org/10.1379/CSC-99r.1 . Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications DR Ciocca , GM Clark , AK Tandon , SA Fuqua , WJ Welch , WL McGuire . Heat shock protein hsp70 in patients with axillary lymph node-negative breast cancer: prognostic implications . J Natl Cancer Inst , 1993 . 85 ( 7 ): 570 - 574 . 8455204 DOI: 10.1093/jnci/85.7.570 http://doi.org/10.1093/jnci/85.7.570 . Heat shock protein hsp70 in patients with axillary lymph node-negative breast cancer: prognostic implications QH Dong , S Zheng , Y Hu , GX Chen , JY Ding . Evaluation of ST13 gene expression in colorectal cancer patients . J Zhejiang Univ Sci B , 2005 . 6 ( 12 ): 1170 - 1175 . 16358374 DOI: 10.1631/jzus.2005.B1170 http://doi.org/10.1631/jzus.2005.B1170 . Evaluation of ST13 gene expression in colorectal cancer patients C Esser , S Alberti , J Hohfeld . Cooperation of molecular chaperones with the ubiquitin/proteasome system . Biochim Biophys Acta, Mol Cell Res , 2004 . 1695 ( 1-3 ): 171 - 188 . DOI: 10.1016/j.bbamcr.2004.09.020 http://doi.org/10.1016/j.bbamcr.2004.09.020 . Cooperation of molecular chaperones with the ubiquitin/proteasome system CG Evans , S Wisen , JE Gestwicki . Heat shock proteins 70 and 90 inhibit early stages of amyloid beta (1-42) aggregation in vitro . J Biol Chem , 2006 . 281 ( 44 ): 33182 - 33191 . 16973602 DOI: 10.1074/jbc.M606192200 http://doi.org/10.1074/jbc.M606192200 . Heat shock proteins 70 and 90 inhibit early stages of amyloid beta (1-42) aggregation in vitro GH Fan , W Yang , J Sai , A Richmond . Hsc/Hsp70 interacting protein (hip) associates with CXCR2 and regulates the receptor signaling and trafficking . J Biol Chem , 2002 . 277 ( 8 ): 6590 - 6597 . 11751889 DOI: 10.1074/jbc.M110588200 http://doi.org/10.1074/jbc.M110588200 . Hsc/Hsp70 interacting protein (hip) associates with CXCR2 and regulates the receptor signaling and trafficking BC Freeman , MP Myers , R Schumacher , RI Morimoto . Identification of a regulatory motif in Hsp70 that affects ATPase activity, substrate binding and interaction with HDJ-1 . EMBO J , 1995 . 14 ( 10 ): 2281 - 2292 . 7774586 . Identification of a regulatory motif in Hsp70 that affects ATPase activity, substrate binding and interaction with HDJ-1 J Frydman , J Höhfeld . Chaperones get in touch: the Hip-Hop connection . Trends Biochem Sci , 1997 . 22 ( 3 ): 87 - 92 . 9066258 DOI: 10.1016/S0968-0004(97)01005-0 http://doi.org/10.1016/S0968-0004(97)01005-0 . Chaperones get in touch: the Hip-Hop connection FU Hartl . Molecular chaperones in cellular protein folding . Nature , 1996 . 381 ( 6583 ): 571 - 579 . 8637592 DOI: 10.1038/381571a0 http://doi.org/10.1038/381571a0 . Molecular chaperones in cellular protein folding MP Hernandez , WP Sullivan , DO Toft . The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex . J Biol Chem , 2002 . 277 ( 41 ): 38294 - 38304 . 12161444 DOI: 10.1074/jbc.M206566200 http://doi.org/10.1074/jbc.M206566200 . The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex J Höhfeld , S Jentsch . GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1 . EMBO J , 1997 . 16 ( 20 ): 6209 - 6216 . 9321400 DOI: 10.1093/emboj/16.20.6209 http://doi.org/10.1093/emboj/16.20.6209 . GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1 J Höhfeld , Y Minami , FU Hartl . Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle . Cell , 1995 . 83 ( 4 ): 589 - 598 . 7585962 DOI: 10.1016/0092-8674(95)90099-3 http://doi.org/10.1016/0092-8674(95)90099-3 . Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle H Irmer , J Höhfeld . Characterization of functional domains of the eukaryotic co-chaperone Hip . J Biol Chem , 1997 . 272 ( 4 ): 2230 - 2235 . 8999928 DOI: 10.1074/jbc.272.4.2230 http://doi.org/10.1074/jbc.272.4.2230 . Characterization of functional domains of the eukaryotic co-chaperone Hip M Jäättelä . Escaping cell death: survival proteins in cancer . Exp Cell Res , 1999 . 248 ( 1 ): 30 - 43 . 10094811 DOI: 10.1006/excr.1999.4455 http://doi.org/10.1006/excr.1999.4455 . Escaping cell death: survival proteins in cancer M Jäättelä , D Wissing , K Kokholm , T Kallunki , M Egeblad . Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases . EMBO J , 1998 . 17 ( 21 ): 6124 - 6134 . 9799222 DOI: 10.1093/emboj/17.21.6124 http://doi.org/10.1093/emboj/17.21.6124 . Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases KC Kanelakis , PJ Murphy , MD Galigniana , Y Morishima , S Takayama , JC Reed , DO Toft , WB Pratt . Hsp70 interacting protein Hip does not affect glucocorticoid receptor folding by the hsp90-based chaperone machinery except to oppose the effect of BAG-1 . Biochemistry , 2000 . 39 ( 46 ): 14314 - 14321 . 11087380 DOI: 10.1021/bi001671c http://doi.org/10.1021/bi001671c . Hsp70 interacting protein Hip does not affect glucocorticoid receptor folding by the hsp90-based chaperone machinery except to oppose the effect of BAG-1 A Klettner . The induction of heat shock proteins as a potential strategy to treat neurodegenerative disorders . Drug News Perspect , 2004 . 17 ( 5 ): 299 - 306 . 15334179 DOI: 10.1358/dnp.2004.17.5.829033 http://doi.org/10.1358/dnp.2004.17.5.829033 . The induction of heat shock proteins as a potential strategy to treat neurodegenerative disorders H Kosano , B Stensgard , MC Charlesworth , N McMahon , D Toft . The assembly of progesterone receptor-hsp90 complexes using purified proteins . J Biol Chem , 1998 . 273 ( 49 ): 32973 - 32979 . 9830049 DOI: 10.1074/jbc.273.49.32973 http://doi.org/10.1074/jbc.273.49.32973 . The assembly of progesterone receptor-hsp90 complexes using purified proteins G Li , SZ Zhang . The different expression of the tumor suppressor gene ST13 in colon cancer and adjacent tumor tissue . Shiyong Zhongliu Zazhi , 2000 . 15 ( 4 ): 262 - 263 . (in Chinese) . The different expression of the tumor suppressor gene ST13 in colon cancer and adjacent tumor tissue MP Mayer , B Bukau . Hsp70 chaperones: cellular functions and molecular mechanism . CMLS Cell Mol Life Sci , 2005 . 62 ( 6 ): 670 - 684 . DOI: 10.1007/s00018-004-4464-6 http://doi.org/10.1007/s00018-004-4464-6 . Hsp70 chaperones: cellular functions and molecular mechanism Y Mo , S Zheng , D Shen . Differential expression of HSU17714 gene in colorectal cancer and normal colonic mucosa . Zhonghua Zhongliu Zazhi , 1996 . 18 ( 4 ): 241 - 243 . (in Chinese) 9387309 . Differential expression of HSU17714 gene in colorectal cancer and normal colonic mucosa YQ Mo , S Zheng , DJ Shen , XH Cai , J Cao , LJ Zhu . The expression of p53 and HSU17714 mRNA in colon cancer and normal tissue . Aizheng , 1997 . 16 ( 1 ): 12 - 15 . (in Chinese) . The expression of p53 and HSU17714 mRNA in colon cancer and normal tissue YQ Mo , L Zheng , XH Cai . Expression of HSU17714 gene in colorectal cancer and other tumors . Zhongguo Zhongliu Linchuang , 1997 . 24 ( 7 ): 504 - 508 . (in Chinese) . Expression of HSU17714 gene in colorectal cancer and other tumors S Murata , Y Minami , M Minami , T Chiba , K Tanaka . CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein . EMBO Rep , 2001 . 2 ( 12 ): 1133 - 1138 . 11743028 DOI: 10.1093/embo-reports/kve246 http://doi.org/10.1093/embo-reports/kve246 . CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein S Murata , T Chiba , K Tanaka . CHIP: a quality-control E3 ligase collaborating with molecular chaperones . Int J Biochem Cell Biol , 2003 . 35 ( 5 ): 572 - 578 . 12672450 DOI: 10.1016/S1357-2725(02)00394-1 http://doi.org/10.1016/S1357-2725(02)00394-1 . CHIP: a quality-control E3 ligase collaborating with molecular chaperones L Neckers , K Neckers . Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics–an update . Expert Opin Emerg Drugs , 2005 . 10 ( 1 ): 137 - 149 . 15757409 DOI: 10.1517/14728214.10.1.137 http://doi.org/10.1517/14728214.10.1.137 . Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics–an update GM Nelson , V Prapapanich , PE Carrigan , PJ Roberts , DL Riggs , DF Smith . The heat shock protein 70 cochaperone hip enhances functional maturation of glucocorticoid receptor . Mol Endocrinol , 2004 . 18 ( 7 ): 1620 - 1630 . 15071092 DOI: 10.1210/me.2004-0054 http://doi.org/10.1210/me.2004-0054 . The heat shock protein 70 cochaperone hip enhances functional maturation of glucocorticoid receptor EA Nollen , AE Kabakov , JF Brunsting , B Kanon , J Hohfeld , HH Kampinga . Modulation of in vivo HSP70 chaperone activity by Hip and Bag-1 . J Biol Chem , 2001 . 276 ( 7 ): 4677 - 4682 . 11076956 DOI: 10.1074/jbc.M009745200 http://doi.org/10.1074/jbc.M009745200 . Modulation of in vivo HSP70 chaperone activity by Hip and Bag-1 J Nylandsted , M Rohde , K Brand , L Bastholm , F Elling , M Jäättelä . Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2 . Proc Natl Acad Sci USA , 2000 . 97 ( 14 ): 7871 - 7876 . DOI: 10.1073/pnas.97.14.7871 http://doi.org/10.1073/pnas.97.14.7871 . Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2 V Prapapanich , S Chen , SC Nair , RA Rimerman , DF Smith . Molecular cloning of human p48, a transient component of progesterone receptor complexes and an Hsp70-binding protein . Mol Endocrinol , 1996 . 10 ( 4 ): 420 - 431 . 8721986 DOI: 10.1210/me.10.4.420 http://doi.org/10.1210/me.10.4.420 . Molecular cloning of human p48, a transient component of progesterone receptor complexes and an Hsp70-binding protein V Prapapanich , S Chen , EJ Toran , RA Rimerman , DF Smith . Mutational analysis of the hsp70-interacting protein Hip . Mol Cell Biol , 1996 . 16 ( 11 ): 6200 - 6207 . 8887650 . Mutational analysis of the hsp70-interacting protein Hip V Prapapanich , S Chen , DF Smith . Mutation of Hip’s carboxy-terminal region inhibits a transitional stage of progesterone receptor assembly . Mol Cell Biol , 1998 . 18 ( 2 ): 944 - 952 . 9447991 . Mutation of Hip’s carboxy-terminal region inhibits a transitional stage of progesterone receptor assembly ZZ Shi , S Zheng , XH Cai , 等 . Application of Subtractive Hybridization Technique in Screening for Human Colorectal Cancer-Related Genes . Proceedings of the First Conference of Chinese Cancer Research Foundation (CCRF) , 1992 . : Quiyang, China 157 Abstract (in Chinese) . Application of Subtractive Hybridization Technique in Screening for Human Colorectal Cancer-Related Genes DF Smith . Dynamics of heat shock protein 90-progesterone receptor binding and the disactivation loop model for steroid receptor complexes . Mol Endocrinol , 1993 . 7 ( 11 ): 1418 - 1429 . 7906860 DOI: 10.1210/me.7.11.1418 http://doi.org/10.1210/me.7.11.1418 . Dynamics of heat shock protein 90-progesterone receptor binding and the disactivation loop model for steroid receptor complexes DF Smith , L Whitesell , SC Nair , S Chen , V Prapapanich , RA Rimerman . Progesterone receptor structure and function altered by gsdanamycin, an hsp90 binding agent . Mol Cell Biol , 1995 . 15 ( 12 ): 6804 - 6812 . 8524246 . Progesterone receptor structure and function altered by gsdanamycin, an hsp90 binding agent C Sõti , E Nagy , Z Giricz , L Vigh , P Csermely , P Ferdinandy . Heat shock proteins as emerging therapeutic targets . Br J Pharmacol , 2005 . 146 ( 6 ): 769 - 780 . 16170327 DOI: 10.1038/sj.bjp.0706396 http://doi.org/10.1038/sj.bjp.0706396 . Heat shock proteins as emerging therapeutic targets S Takayama , Z Xie , JC Reed . An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators . J Biol Chem , 1999 . 274 ( 2 ): 781 - 786 . 9873016 DOI: 10.1074/jbc.274.2.781 http://doi.org/10.1074/jbc.274.2.781 . An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators WJ Tissing , JP Meijerink , ML den Boer , B Brinkhof , R Pieters . mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL . Leukemia , 2005 . 19 ( 5 ): 727 - 733 . 15759037 DOI: 10.1038/sj.leu.2403681 http://doi.org/10.1038/sj.leu.2403681 . mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL LM Vargas-Roig , MA Fanelli , LA Lopez , FE Gago , O Tello , JC Aznar , DR Ciocca . Heat shock proteins and cell proliferation in human breast cancer biopsy samples . Cancer Detect Prev , 1997 . 21 ( 5 ): 441 - 451 . 9307847 . Heat shock proteins and cell proliferation in human breast cancer biopsy samples M Velten , BO Villoutreix , MM Ladjimi . Quaternary structure of the HSC70 cochaperone HIP . Biochemistry , 2000 . 39 ( 2 ): 307 - 315 . 10630990 DOI: 10.1021/bi9917535 http://doi.org/10.1021/bi9917535 . Quaternary structure of the HSC70 cochaperone HIP M Velten , N Gomez-Vrielynck , A Chaffotte , MM Ladjimi . Domain structure of the HSC70 cochaperone, HIP . J Biol Chem , 2002 . 277 ( 1 ): 259 - 266 . 11687574 DOI: 10.1074/jbc.M106881200 http://doi.org/10.1074/jbc.M106881200 . Domain structure of the HSC70 cochaperone, HIP LB Wang , S Zheng , SZ Zhang , JP Peng , F Ye , SC Fang , JM Wu . Expression of ST13 in colorectal cancer and adjacent normal tissues . World J Gastroenterol , 2005 . 11 ( 3 ): 336 - 339 . 15637739 . Expression of ST13 in colorectal cancer and adjacent normal tissues Y Zhang , X Cai , B Schlegelberger , S Zheng . Assignment of human putative tumor suppressor genes ST13 (alias SNC6) and ST14 (alias SNC19) to human chromosome bands 22q13 and 11q24→q25 by in situ hybridization . Cytogenet Cell Genet , 1998 . 83 ( 1-2 ): 56 - 57 . 9925927 DOI: 10.1159/000015125 http://doi.org/10.1159/000015125 . Assignment of human putative tumor suppressor genes ST13 (alias SNC6) and ST14 (alias SNC19) to human chromosome bands 22q13 and 11q24→q25 by in situ hybridization S Zheng , XH Cai , ZZ Shi , 等 . Application of Subtractive Hybridization in Screening for Colorectal Cancer-Related Genes . Proceedings of the Fourth Sino-Japanese Symposium on Colorectal Cancer , 1994 . : Hangzhou, China Abstract, E1 (in Chinese) . Application of Subtractive Hybridization in Screening for Colorectal Cancer-Related Genes S Zheng , X Cai , J Cao , L Zheng , L Geng , Y Zhang , J Gu , Z Shi . Screening and identification of down-regulated genes in colorectal carcinoma by subtractive hybridization: a method to identify putative tumor suppressor genes . Chin Med J , 1997 . 110 ( 7 ): 543 - 547 . 9594214 . Screening and identification of down-regulated genes in colorectal carcinoma by subtractive hybridization: a method to identify putative tumor suppressor genes S Zheng , J Shao , Q Dong , J Peng , SZ Zhang . Characterization of ST13 protein expression in human colorectal cancer tissues . Chin German J Clin Oncol , 2005 . 4 ( 1 ): 1 - 7 . DOI: 10.1007/s10330-004-0347-4 http://doi.org/10.1007/s10330-004-0347-4 . Characterization of ST13 protein expression in human colorectal cancer tissues The authors would like to thank Ms. Stephanie Moses for her help in English editing. 10.1631/jzus.2007.B0170 Project supported by the National Basic Research Program (973) of China (No. 2004CB518707) and the National Natureal Science Foundation of China (No. 30400521) 2006-12-06 2007-01-10 2022-01-05 Copyright © 2007, Journal of Zhejiang University Science 2007 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 03 08