Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

TPD52 (tumor D52) Austin Della-Franca, Jennifer Byrne Children's Cancer Research Unit, Kids Research Institute, The Childrenis Hospital at Westmead, Sydney, Australia (ADF, JB)

Published in Atlas Database: September 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/TPD52ID42676ch8q21.html DOI: 10.4267/2042/45033 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology

13-acetate (TPA) (Byrne et al., 1996), myc onco- Identity protein overexpression (Guo et al., 2000) and MyoD Other names: D52, N8L, PC-1, PrLZ, hD52 knockdown (Asakura et al., 2007). HGNC (Hugo): TPD52 Pseudogene Location: 8q21.13 No human pseudogene for TPD52 has been identified Local order: On the reverse strand. (see Pseudogene In Family). DNA/RNA Protein Description Description The TPD52 gene is found on 8, at The TPD52 gene encodes multiple , location 81109658-81246391 bp. It is composed of at predominantly TPD52 (184 aa, isoform 3, accession no. least 9 exons spanning a genomic region of 138.88 kb NP_005070.1) and PrLZ/PC-1 (224 aa, isoform 1, and the open reading frame of the coding region is 555 accession no. NP_001020423.1). Both are encoded by bp. 6 exons, with the first exon being unique to each isoform. They share a coiled-coil motif located towards Transcription the N-terminus but possess alternate N-terminal Experimentally, an increase in TPD52 protein or domains. Since TPD52 is more ubiquitously expressed mRNA transcript levels has been demonstrated or than PrLZ (for TPD52 expression, see Byrne et al., predicted following a number of different types of 1995 and Chen et al., 1996; for PrLZ expression, see stimuli, such as hormone receptor activation(using Wang et al., 2004), TPD52 will be the primary focus of dihydrotestosterone (DePrimo et al., 2002), estradiol this summary. (Byrne et al., 1996) and the synthetic androgens R1881 TPD52 is a 184-amino acid polypeptide with a (DePrimo et al., 2002; Nelson et al., 2002; Rubin et al., predicted molecular mass of 19.8 kDa. The protein is 2004) and methyltrienolone (Wang et al., 2004)), indicated to be largely hydrophilic, has a calculated immune receptor activation (toll-like receptor 4 (TLR- isoelectric point of 4.75, and contains an identified 4) using bacterial Lipopolysaccharide (LPS) and phosphorylation site at Serine 136 (Chew et al., 2008; triggering receptors expressed on myeloid cells 1 Thomas et al., 2010). (TREM-1) using anti-TREM-1 cross-linking antibody Using glutaraldehyde cross-linking, Chen et al. (1997) (Dower et al., 2008)), Erbb2 over-expression (Landis et showed that TPD52 is able to bind itself (also shown by al., 2005), Platelet-Derived Growth Factor (PDGF) Byrne et al., 1998; Sathasivam et al., 2001, and Thomas signalling (Ma et al., 2005) and BRCA1 tumor et al., 2001). Byrne et al. (1998) also showed that suppressor (containing a single amino acid substitution TPD52 binds the related TPD52L1 and TPD52L2 specifically at Ser1841Asn) expression (Crugliano et proteins. These authors proposed that TPD52 may exert al., 2007). A decrease in TPD52 transcript levels has and/or regulate its activities through interaction with been observed or predicted following treatment with itself and its related proteins and that the coiled-coil the differentiating agent 12-O-tetradecanoylphorbol- motif predicted within the TPD52 protein is necessary

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6) 483 TPD52 (tumor protein D52) Della-Franca A, Byrne J

for interactions (Byrne et al., 1998). A subsequent tissues and in cultured mucosal T84 cells of the rat analysis indicated that C-terminal regions may also (Groblewski et al., 1999; Kaspar et al., 2003a). Kaspar facilitate and/or stabilise these interactions (Sathasivam et al. (2003a) also showed that TPD52 exists in et al., 2001). perinuclear regions of T84 cells, whilst Thomas et al. The first heterologous binding partner identified for (2004) showed that TPD52 exists within or around both TPD52 was the proteolipid MAL2 (Wilson et al., endocytic and exocytic compartments within rat 2001), which is similar to MAL, an integral component pancreatic acinar cells. Using breast cancer samples, of the apical transport machinery in polarised cell types immunohistochemical analysis by Balleine et al. (2000) (Martin-Belmonte et al., 1998; Puertollano et al., 1999; revealed TPD52 staining within the cytoplasm and less Cheong et al., 1999). MAL2 was shown to be a binding frequently in the perinucleus, whilst benign epithelial partner for TPD52 using the yeast two-hybrid system elements displayed little or no staining. Myeloma cells (Wilson et al., 2001) and more recently to co- also strongly expressed TPD52 in the cytoplasm immunoprecipitate with TPD52 using Myc-MAL2 (Tiacci et al., 2005). overexpressing MCF-10A breast cancer cells (Fanayan Function et al., 2009). TPD52 also binds Annexin VI, which is involved in At a subcellular level, TPD52 appears to be involved in membrane trafficking, and this binding is Ca 2+ - plasma membrane-based exocytic (Thomas et al., 2001; dependent (Thomas et al., 2002; Tiacci et al., 2005). Kaspar et al., 2003a; Kaspar et al., 2003b; Chew et al., TPD52 (along with Tip47, Rab5, Rab6 and Rab9) co- 2008) and endocytic functions (Thomas et al., 2004), immunoprecipitated with the bacterial product ExoS, as and trafficking within the exo- and endocytic pathways shown by a study which examined the transport of (Thomas et al., 2002; Thomas et al., 2004). At a ExoS from plasma membrane to perinuclear regions cellular level, TPD52 has been shown to promote (Zhang et al., 2007a). proliferation (Lewis et al., 2007; Zhang et al., 2007b; Shehata et al., 2008a; Li et al., 2009) and tissue Expression invasion (Lewis et al., 2007), as well as B-cell Early studies using Northern blot analysis undertaken maturation (Tiacci et al., 2005). However, a clear link by Byrne et al. (1995) showed strong expression of between TPD52's subcellular and cellular influences TPD52 transcripts in colon and kidney tissues. Chen et has yet to be established. al. (1996) used the same technique to identify TPD52 was initially predicted to function as a calcium- comparatively high TPD52 transcript levels in kidney, sensitive signalling molecule, since rabbit TPD52 is prostate, small intestine and kidney, as well as phosphorylated in gastric parietal cells upon moderate levels in brain, liver, placenta, pancreas cholinergic stimulation (Parente et al., 1996). At least epithelia, and low levels in heart, lung, ovary, two phosphorylation events for human and rat TPD52 peripheral blood leukocyte, skeletal muscle, spleen, have been demonstrated (Groblewski et al., 1996; testis, and thymus tissues. Chen et al. (1997) followed Kaspar et al., 2003a; 2003b) and more are predicted up with immunohistochemistry and multiple tissue (Olsen et al., 2006; Molina et al., 2007). Using mass western blot analysis indicating strong detection of spectrometry and site-directed mutagenesis, Chew et al. TPD52 protein in colon and kidney, moderate levels in (2008) showed that the calcium/calmodulin-dependent brain and liver tissue, and low levels in heart, lung and phosphorylation of TPD52 on serine residue 136 may skeletal muscle. Groblewski et al. (1999) used western be mediated by CAMK2delta6. Significantly, the time- blotting and immunofluorescence studies to identify course of such phosphorylation was found to correlate high levels of TPD52 protein in colon epithelia and with exocytosis, suggesting that TPD52 may promote small intestine epithelia, as well as moderate expression exocytosis following phosphorylation. Thomas et al. in the lacrimal gland, pancreas, parotid gland, stomach (2010) recently showed that this phosphorylation of epithelia and submandibular gland. More recently, TPD52 caused an increase of LAMP-1 exocytosis from Wang et al. (2004) identified high levels of the PrLZ CHO-K1 cells. This had earlier been suggested in transcript in prostate using a multiple tissue expression studies involving stimulation of pancreatic (using array, whilst Tiacci et al. (2005) found high levels of cholecystokinin-octapeptide) and colonic (using TPD52 protein via immunofluorescence in B cells carbachol) secretion in rat acinar and mucosal T-84 (including plasma cells) and colon tissue, and moderate cells, respectively (Kaspar et al., 2003a; 2003b). On par levels in stomach and pancreas epithelia. with this, amylase was shown to be released from rat Localisation pancreatic acinar cells in a calcium-dependent manner, following the introduction of recombinant TPD52 TPD52 is partitioned between soluble and insoluble (Thomas et al., 2001). Furthermore, TGF-beta1 was cellular protein fractions (Groblewski et al., 1999; found to be secreted from stably transfected mouse Balleine et al., 2000), suggesting that TPD52 may have Tpd52-expressing 3T3 fibroblasts (Lewis et al., 2007). multiple subcellular locations. TPD52 is abundant However, it has not been determined if TPD52 is around secretory granules in the apical cytoplasm of directly involved with the above-mentioned release of epithelial cells of exocrine glands, gastrointestinal

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6) 484 TPD52 (tumor protein D52) Della-Franca A, Byrne J

TGF-beta1 or if this is perhaps a downstream found in Drosophila melanogaster and Caenorhabditis consequence of TPD52 expression. elegans through gene duplication events (Boutros et al., TPD52 binds Annexin VI (Thomas et al., 2002; Tiacci 2004). et al., 2005) and MAL2 (Wilson et al., 2001) which have been implicated in clathrin-mediated endocytosis Implicated in (Kamal et al., 1998; Thomas et al., 2002) and indirect apical transcytosis (de Marco et al., 2002), respectively. Various cancers Using CCK-8 treatment in pancreatic acinar cells, Note Thomas et al. (2004) showed TPD52 to localise to early Association to diseases (breast neoplasms; carcinoma, endosomes and the limiting membrane of zymogen basal cell; neoplasms; ovarian neoplasms; prostatic granules, suggesting that TPD52 may play a role in neoplasms) and proposed to participate in processes protein and phospholipid distribution within the (anatomical structure morphogenesis, B cell secretory pathway. They also recently examined differentiation, secretion). LAMP-1 trafficking and AP-3/TPD52 co-localisation Disease in CHO-K1 cells which suggested TPD52 may In situ hybridisation and Northern blot studies first participate in lysosome-like vesicle formation (post- revealed TPD52 overexpression in breast cancer (Byrne golgi) as well as endocytic retrieval (Thomas et al., et al., 1995). Chen et al. (1996, 1997) also found 2010). TPD52's potential endocytic involvement was TPD52 mRNA/protein to be expressed in breast cancer also demonstrated through its co-immunoprecipitation derived cell lines, as well as those derived from lung with the bacterial product ExoS (along with Tip47, cancer, colon cancer, pancreatic cancer, prostate Rab5, Rab6 and Rab9), perhaps enabling the transport cancer, kidney cancer, leukemia and Burkitt's of the bacterial product ExoS from endosome to golgi lymphoma. Other more recent investigations have and perinuclear regions (Zhang et al., 2007a). TPD52 confirmed TPD52 or PrLZ RNA/protein also binds family member TPD52L1, which itself has overexpression in prostate cancer (Rubin et al., 2004; been implicated in the regulation of SNARE complexes Wang et al., 2004). on early endosomes (Proux-Gillardeaux et al., 2003). TPD52 overexpression has also been predicted via Exogenous expression of TPD52 isoforms in various expression microarray studies for prostate (Rhodes et cell lines has produced increases in anchorage- al., 2002; Ahram et al., 2002; Best et al., 2003), ovarian independent colony formation (Lewis et al., 2007; (Shridhar et al., 2001), endometrial (Risinger et al., Zhang et al., 2007b; Shehata et al., 2008a), 2003; Cai et al., 2007), hepatocellular (Chen et al., proliferation (Lewis et al., 2007; Zhang et al., 2007b; 2002), lung (Garber et al., 2001; Bhattacharjee et al., Shehata et al., 2008a; Li et al., 2009), metastatic ability 2001), melanoma (Bittner et al., 2000; Zhou et al., post-inoculation (Lewis et al., 2007), tumor volume 2004; Hoek, 2007; Roesch et al., 2007) and testicular post-inoculation (Zhang et al., 2007b; Li et al., 2009) germ cell tumours (Sperger et al., 2003; Skotheim et and migration/invasion rate (Li et al., 2009). Also, a al., 2005; Korkola et al., 2006; Skotheim et al., 2006; decrease in TPD52 level following siRNA treatment McIntyre et al., 2007; Korkola et al., 2008). TPD52 caused an increase in apoptosis in the SK-BR-3 breast protein overexpression has been confirmed in cancer cell line (Shehata et al., 2008a). Zhang et al. melanoma (Roesch et al., 2007) and testicular germ cell (2007b) showed that stable transfection of TPD52 in tumours (Alagaratnam et al., 2009). LNCaP and its derivative androgen-independent C4-2 prostate cancer cell lines results in the phosphorylation Prognosis of signalling intermediates that are also implicated in Expression microarray studies have revealed TPD52 producing the above-mentioned phenotypes, namely gene overexpression to be associated with adverse AKT, Raf and GSK-3beta. The increased outcome for patients with breast cancer (Adler et al., phosphorylation of AKT has since been confirmed by 2006; Liu et al., 2007), prostate cancer (Bismar et al., Ummanni et al. (2008), who also examined the LNCaP 2006) and mantle cell lymphoma (Ma et al., 2007). cell line. Higher levels of TPD52 expression amongst breast cancer patients has also been shown to be associated Homology with reduced overall patient survival (Shehata et al., Subsequent to the characterisation of TPD52 in 1995 2008a). (Byrne et al., 1995), there have been three Cytogenetics related described. These are TPD52L1 (D53) Using TPD52 expression and relative TPD52 copy (Byrne et al., 1996), TPD52L2 (D54) (Nourse et al., number studies in breast specimens, Balleine et al. 1998) and NYD-SP25/TPD52L3 (D55) (Cao et al., (2000) first proposed TPD52 as a target gene driving 2006). TPD52-like genes share about 50% nucleotide increased copy number of 8q21. Similar studies have sequence homology, and are not similar to proteins of since identified an association between TPD52 copy known function in any species (Nourse et al., 1998). number gain and TPD52 expression in prostate cancer TPD52 and TPD52-like genes appear to have evolved (Rubin et al., 2004; Wang et al., 2004) and ovarian from ancestral TPD52-like sequences such as those

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6) 485 TPD52 (tumor protein D52) Della-Franca A, Byrne J

cancer (Byrne et al., 2005). TPD52 has also been found yeast two-hybrid system. Oncogene. 1998 Feb 19;16(7):873- to be amplified and overexpressed in multiple myeloma 81 (Largo et al., 2006), pancreatic cancer xenografts Kamal A, Ying Y, Anderson RG. Annexin VI-mediated loss of (Loukopolous et al., 2007) and testicular germ cell spectrin during coated pit budding is coupled to delivery of LDL tumours (Skotheim et al., 2006; Mcintyre et al., 2007; to lysosomes. J Cell Biol. 1998 Aug 24;142(4):937-47 Korkola et al., 2008). However, TPD52 overexpression Martín-Belmonte F, Kremer L, Albar JP, Marazuela M, Alonso may also occur in the absence of gene amplification or MA. Expression of the MAL gene in the thyroid: the MAL proteolipid, a component of glycolipid-enriched membranes, is gain (Balleine et al., 2000; Adelaide et al., 2007). apically distributed in thyroid follicles. Endocrinology. 1998 Oncogenesis Apr;139(4):2077-84 An increase in TPD52 expression has been found to be Nourse CR, Mattei MG, Gunning P, Byrne JA. Cloning of a a comparatively early event in breast (Porter et al., third member of the D52 gene family indicates alternative 2003; Yu et al., 2004; Shehata et al., 2008a), prostate coding sequence usage in D52-like transcripts. Biochim Biophys Acta. 1998 Nov 26;1443(1-2):155-68 (Rubin et al., 2004; Wang et al., 2004) and ovarian cancer (Byrne et al., 2005). Other analyses also suggest Cheong KH, Zacchetti D, Schneeberger EE, Simons K. that increased TPD52 expression may be a marker of VIP17/MAL, a lipid raft-associated protein, is involved in apical transport in MDCK cells. Proc Natl Acad Sci U S A. 1999 May tumour predisposition (Sims et al., 2007) or very early 25;96(11):6241-8 preneoplastic changes (Byrne et al., 2005). High Groblewski GE, Yoshida M, Yao H, Williams JA, Ernst SA. TPD52 expression may also contribute to the Immunolocalization of CRHSP28 in exocrine digestive glands development of primary carcinomas (Rubin et al., and gastrointestinal tissues of the rat. Am J Physiol. 1999 2004; Wang et al., 2004; Bismar et al., 2006; Wang et Jan;276(1 Pt 1):G219-26 al., 2007). The prevalence of high TPD52 expression in Puertollano R, Martín-Belmonte F, Millán J, de Marco MC, early and late stages of cancer suggest that it may Albar JP, Kremer L, Alonso MA. The MAL proteolipid is contribute to tumour initiation and progression, necessary for normal apical transport and accurate sorting of possibly through independent mechanisms. It would be the influenza virus hemagglutinin in Madin-Darby canine kidney cells. J Cell Biol. 1999 Apr 5;145(1):141-51 expected that TPD52 perturbs fundamental cell properties, as TPD52 overexpression exists in tumours Balleine RL, Fejzo MS, Sathasivam P, Basset P, Clarke CL, Byrne JA. 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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6) 487 TPD52 (tumor protein D52) Della-Franca A, Byrne J

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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6) 488 TPD52 (tumor protein D52) Della-Franca A, Byrne J

Ummanni R, Teller S, Junker H, Zimmermann U, Venz S, Li L, Zhang D, Zhang L, Zhu G, Sun Y, Wu K, Wang X, He D. Scharf C, Giebel J, Walther R. Altered expression of tumor PrLZ expression is associated with the progression of prostate protein D52 regulates apoptosis and migration of prostate cancer LNCaP cells. Mol Carcinog. 2009 May;48(5):432-40 cancer cells. FEBS J. 2008 Nov;275(22):5703-13 Thomas DD, Martin CL, Weng N, Byrne JA, Groblewski GE. Alagaratnam S, Hardy JR, Lothe RA, Skotheim RI, Byrne JA. Tumor protein D52 expression and Ca2+-dependent TPD52, a candidate gene from genomic studies, is phosphorylation modulates lysosomal membrane protein overexpressed in testicular germ cell tumours. Mol Cell trafficking to the plasma membrane. Am J Physiol Cell Physiol. Endocrinol. 2009 Jul 10;306(1-2):75-80 2010 Mar;298(3):C725-39

Fanayan S, Shehata M, Agterof AP, McGuckin MA, Alonso This article should be referenced as such: MA, Byrne JA. Mucin 1 (MUC1) is a novel partner for MAL2 in breast carcinoma cells. BMC Cell Biol. 2009 Jan 28;10:7 Della-Franca A, Byrne J. TPD52 (tumor protein D52). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6):483-489.

Atlas Genet Cytogenet Oncol Haematol. 2011; 15(6) 489