The tumor protein D52 family: many pieces, many puzzles

BBRC Biochemical and Biophysical Research Communications 325 (2004) 1115–1121 www.elsevier.com/locate/ybbrc

Breakthroughs and Views

The tumor protein D52 family: many pieces, many puzzles Rose Boutrosa,b, Susan Fanayana, Mona Shehataa,b, Jennifer A. Byrnea,b,* a

Molecular Oncology Laboratory, Oncology Research Unit, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead 2145, NSW, Australia The University of Sydney Discipline of Paediatrics and Child Health, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead 2145, NSW, Australia

b

Received 29 September 2004 Available online 6 November 2004

Abstract Tumor protein D52-like proteins are small coiled-coil motif bearing proteins which are conserved from lower organisms to human. The founding member of the family, human D52, has principally attracted research interest due to its frequent overexpression in cancer, often in association with D52 gene amplification. This review summarises published literature concerning this protein family since their discovery, which is highlighting an increasing diversity of functions for D52-like proteins. This in turn highlights a need for more comparative functional analyses, to determine which functions are conserved and which may be isoform-specific. This knowledge will be crucial for any future manipulation of D52 function in human disease, including cancer. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Tumor protein D52; N8; R10; CSPP28; CRHSP28; Chromosome 8q21; Breast carcinoma; Prostate carcinoma

Genome projects have highlighted the frequency of gene families in higher organisms, and a major challenge is to now understand why single orthologues in lower organisms become multiple paralogues in higher organisms, which are in addition frequently alternatively spliced. To add to this complexity, many single gene products, particularly adaptor proteins, are themselves multi-functional, which renders elucidating the functions of any gene family an extremely challenging task. These challenges are exemplified by considering the tumor protein D52 family, which is emerging as a new family of adaptor molecules.

Gene identification, nomenclature, and sequence characteristics The first D52-like gene was identified nearly 10 years ago [1], and related genes in different species have been *

Corresponding author. Fax: +61 2 9845 3078. E-mail address: [email protected] (J.A. Byrne).

0006-291X/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2004.10.112

subsequently identified at a steady rate. As numerous independent groups have identified these sequences, different names have been assigned to members of orthologous groups and/or products of single genes. This nomenclature is summarised in Table 1, which also categorises D52-like sequences according to orthologous groups, and includes official designations for sequences where available. For simplicity, this review will employ the terms used to name these sequences when they were first identified, namely D52 [1], D53 [2,3], and D54 [4,5]. Mammalian D52-like sequences uniformly encode small hydrophilic polypeptides which are generally between 180 and 200 residues in length [2,5]. These typically include a coiled-coil motif of approximately 50 amino acids, and N- and C-terminally located PEST sequences, which have been linked with regulating protein stability [2]. The coiled-coil motif is required for homoand heteromeric interactions with other D52-like proteins, and other heterologous partners [4,6–8]. D52-like sequences are primarily conserved within their central regions, which include the coiled-coil motif. The C-terminal regions are most clearly divergent, both between

different D52-like proteins in a single species and orthologous D52-like proteins [2,5]. Whereas 3 human D52like genes have been identified, and a fourth gene (NYD-SP25) is predicted, only single D52-like orthologues have been identified in Drosophila melanogaster and Caenorhabditis elegans (Table 1). Phylogenetic analyses indicate that vertebrate D52, D53, and D54 sequences have arisen from ancestral D52-like sequences through gene duplication events, and that NYD-SP25 sequences may have arisen more recently through duplication of a D54 gene (Fig. 1).

Sequence names recognised as official designations are asterisked.

Bmo.857, CG5174 [44], Dm.7079, F13E6.1, XL294, Cel.23059

Cellular functions for D52-like proteins

Ancestral D52-like genes in lower organisms

Dr.4186, Omy.2893, Xl.8331, Xl.2391 R10 [6] Dr.14330, Xl.11696, Xl.10244, Str.17690 Other vertebrates

D53 [8], Gga.256

Mm.158128 Mm.136648, Rn.23937, Ssc.2916, Bt.21340 mD52 [2], Tpd52*, Mm.2777, CRHSP-28 [10], CSPP28 [9], Bt.27864 Other mammals

mD53 [3], Tpd52l1*, Mm.7821

Hs.343593, Hs.351815 hD54 [4,5], TPD52L2*, Hs.154718 hD52 [1], TPD52*, N8, N8L [20], PrLZ [27], PC-1 [59], Hs.162089

hD53 [2], TPD52L1*, +5/1 [4], hD53L1 [47], Hs.16611

NYD-SP25 D52

H. sapiens

Species

Orthologous groups

D53

D54

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Table 1 Summary of nomenclature applied to published D52-like sequences, and Unigene identifiers of associated or additional sequence clusters

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The most frequently identified physiological role for D52 has been the regulation of vesicle trafficking and exocytotic secretion. Rabbit [9] and rat [10] D52 orthologues were identified through being phosphorylated in response to secretory stimuli of gastric parietal and pancreatic acinar cells, respectively. Introduction of recombinant D52 protein into rat pancreatic acinar cells stimulates amylase secretion [11], with D52 also undergoing a rapid translocation from supranuclear to subapical cytoplasmic compartments following secretagogue stimulation of mucosal T84 and rat pancreatic acinar cells [12,13]. D52 and D53 also co-localise with early endosomal markers in rat pancreatic acinar and PC12 cells, respectively [13,8]. Numerous D52 or D53 binding partners, specifically MAL2 [14], the phospholipid-binding protein annexin VI [15], and the SNARE proteins syntaxin 1 and VAMP2 [8], have also been commonly implicated in membrane trafficking and shown to be associated with lipid rafts [16–18], and we have similarly identified that a proportion of D52 expressed in breast carcinoma cell lines partitions within lipid raft-containing fractions [S. Fanayan, unpublished results]. As D53 was found to increase interactions between syntaxin 1 and VAMP2 proteins in vitro [8], and annexin VI has also been proposed to facilitate membrane tethering and fusion [19], D52-like proteins may therefore commonly regulate these processes through binding integral membrane and membrane-associated proteins [8,14,15], and possibly other soluble secretory factors [11]. The earliest reports of D52 sequences also indicate that these are overexpressed in multiple human cancers [1,20]. Human D52 was first identified as overexpressed in human breast carcinoma in a study aiming to identify novel genes implicated in tumor progression in multiple cancer types [1]. Subsequent identification of D52 overexpression in lung cancer [20–22] was an early indication that D52 upregulation is not restricted to breast carcinoma. D52 has since been shown to be overexpressed in prostate [23–27], and ovarian cancer ([28], Byrne et al., manuscript submitted), and is predicted to be also upregulated in endometrial cancer [29] and hepatocellular

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Fig. 1. Phylogenetic analysis of deduced amino acid sequences of D52-like proteins (unrooted tree construction, using the H. magnipapillata sequence as the outgroup), coloured to highlight the separation of vertebrate sequence groups. Sequences were aligned using Clustal W [60], with translated sequences from Unigene clusters being included if the former were indicated to be full-length, and identical to others within the cluster. Subsequent phylogenetic analyses employed the Phylip package [61] accessed using BioManager by ANGIS [http://www.angis.org.au]. Bootstrapped sets of multiple sequence alignments and distance matrices (1000 replicates) were created using the programmes Seqboot and Protdist, respectively. A bootstrapped set of phylogenetic trees (1000 replicates) was then derived using Neighbor, and the consensus tree shown predicted using Consensus.

carcinoma [30]. Expression of rat D52 was also induced in response to Src transformation of 3Y1 fibroblasts [31]. D52 overexpression in breast, prostate, and ovarian cancer is at least partially driven by increased D52 copy number at chromosome 8q21 ([26,27,32,33], Byrne et al., manuscript submitted), and the identification of D52 as a tumor-associated antigen in breast carcinoma may also be related to its status as an amplification target [34,35]. D52-like gene expression has also been linked with proliferation in cancer and virally transduced cells. Links between D52-like gene expression and proliferation arose from the finding that human D52 and D53 transcript levels were reduced in leukemic cell lines treated with a differentiating agent [2], and through the identification of quail D52 as being retrovirally transduced in proliferating neuroepithelial cells [6]. D52 expression has been found to be responsive to estradiol [2] and androgen [26,27,36,37], which are mitogens in the breast and prostate, respectively. A link between D52 expression and estradiol activity in breast carcinoma is also underscored by the fact that D52 clusters with the estrogen receptor and other estrogen-responsive genes in microarray analyses of breast tumors and cell lines [38]. Human D52 expression has been similarly reported to be higher in estrogen receptor-positive than in estrogen receptor-negative breast cancers [39]. We have recently identified D53 as a cell cycle regulated protein in breast carcinoma cell lines, being highly upregulated at the G2-M phase transition, and reduced beyond prometaphase of mitosis [Boutros et al., manuscript in preparation]. This supports previous microarray analyses

which have found D53 expression to be upregulated during the G2 cell cycle phase in fibroblasts [40], to show marked periodic fluctuations in HeLa cells [41,42], and to also vary according to circadian rhythms [43]. Transient expression of pEGFP-tagged D53 isoforms and D52 produced high proportions of multi-nucleated MDA-MB-231 breast carcinoma cells and was associated with D52-like expression persisting throughout mitosis [Boutros et al., manuscript in preparation]. Deregulated expression of D52-like proteins beyond prometaphase may therefore adversely affect cell division. The combined results of targetted functional analyses clearly point to diverse functions for D52-like proteins, to which proteomics and interaction analyses continue to add. The large-scale analysis of interactions between proteins encoded by the D. melanogaster genome showed that the D52 orthologue CG5174 bound numerous proteins in the yeast two-hybrid system, including rad50 and ash1 [44]. Mouse D52 has been identified as localising to interchromatin granule clusters from mouse liver [45], and we have also identified prominent nuclear localisation for human D52 in a subset of ovarian carcinomas [Byrne et al., manuscript submitted]. These findings suggest that D52-like proteins function in subcellular compartments other than the cytoplasm, where their expression has been most frequently identified.

Isoform-specific functions for D52-like proteins Alternative splicing is a hallmark of D52-like transcripts, with large-scale cDNA sequencing projects

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predicting ever-increasing numbers of isoforms which may be expressed from individual D52-like genes. A combination of cDNA cloning and EST database analyses first identified alternatively spliced D52-like sequences [5,6], highlighting two particular sequence insertions initially termed inserts 2 and 3, now known to correspond to alternatively spliced exons [46]. Insert 3 sequences are encoded by 2 short, alternatively spliced exons, one of which encodes a consensus 14-3-3 binding motif. Alternative splicing of this latter exon was shown to regulate binding of D53 isoforms to 14-3-3, identifying alternative splicing as a novel mechanism for regulating 14-3-3 binding which uniquely applies to D52-like proteins [46]. Interactions between D. melanogaster CG5174 and 14-3-3f proteins have also been recently identified [44], and EST analyses predict that alternative splicing also regulates inclusion of a 14-3-3 binding site in CG5174 transcripts [Dm.7079]. The conserved existence of an alternative splicing-based mechanism for regulating 14-3-3 binding may reflect the fact that serine phosphorylation is inadequate for this purpose in the case of D52-like proteins [46]. Interestingly, removal of the 14-3-3 motif-encoding exon from D53 transcripts also removes the adjacent downstream exon and generates a C-terminally truncated protein [46]. This truncated D53 protein has recently been indicated to promote apoptosis through enhancing the kinase activity of ASK1 [47], although it is not yet clear whether this is an isoform-specific function. In contrast, sequences originally designated as insert 2 appear to be restricted to D54 proteins only, and to originate from an alternatively-spliced exon not found in D52 or D53 genes [5,46], or predicted by NYDSP25 sequences (Table 1). Similar alternatively-spliced insertions are however predicted in all ancestral D52like sequences identified or predicted to date (Table 1), further indicating that D52, D53, and NYD-SP25 genes have arisen from ancestral D52-like or D54 genes through duplication-degeneration-complementation events (Fig. 1). The presence of insert 2 duplicates regions of the N- and C-terminal D54 flanking sequences in mammals, Danio rerio, D. melanogaster, and Bombyx mori, and may therefore duplicate a binding motif [5]. The conservation of insert 2 sequences in all ancestral D52-like and vertebrate D54 sequences, and wide tissue distribution of transcripts encoding insert 2 [5], suggest that alternative splicing of insert 2 regulates a fundamental aspect of these proteinsÕ functions. Internal sequence insertions may in fact represent the tip of the iceberg with respect to alternative splicing of D52-like sequences. Alternative N-terminal sequences have been identified for D52 [6,27] and D53 proteins [4], with the inclusion of an alternative N-terminal sequence for human D52 being tissue-specific [27]. Transcripts from the D. melanogaster CG5174 gene are predicted to be extensively alternatively spliced, with

several N-terminal sequences being predicted [Dm.7079]. The longest of these encodes a 150 residue sequence which is not conserved in mammalian D52-like sequences, and shows similarity to R protein transcription factors from plants. Alternative splicing analyses are therefore likely to continue to predict new functions for D52-like proteins [46].

The potential clinical significance of D52 overexpression in cancer Numerous studies now suggest that increased D52 expression may be an early event in cancer which contributes to subsequent tumor progression. D52 expression was found to be generally low in benign prostate lesions, but very frequently elevated in high-grade prostatic intraepithelial neoplasia, prostate carcinomas, and metastases [26,27]. Similarly, microarray analyses have identified D52 as being upregulated at the normal-toductal carcinoma in situ transition in breast carcinoma [48], and increased D52 SAGE tag frequencies were reported in ductal carcinoma in situ, primary invasive breast carcinomas, and metastases [49]. While Best et al. [25] reported that D52 was differentially expressed according to grade in prostate cancer, other studies have found no relationship between D52 expression and clinical parameters [26,27], apart from a trend for high D52 expression to be more frequent in men who undergo subsequent prostate-specific antigen relapse [26]. As many prostate carcinomas strongly expressed D52 in these studies, techniques with a greater dynamic range may be required for detecting associations between D52 expression and clinical parameters. Key questions which remain outstanding are clearly which function(s) of D52 is/are targeted by overexpression in cancer. The combined facts that increased D52 expression appears to be an early event in cancer, and has been linked with positively regulating cell proliferation, another early event in tumor progression, are difficult to overlook. As D54 shares functional characteristics with D52 [4,17], it may also be significant that D54 expression has been reported to have prognostic significance in both breast [50] and pancreatic carcinoma [51], and to be increased in colon cancer [52]. However, D53 is also functionally related to D52 [4,8], is also estradiol-inducible in breast carcinoma cells [2,53–56], and may also regulate cell proliferation [2]. Despite this, with one exception to date [57], D53 does not appear to be consistently up- or down-regulated in cancer [58]. The expression of D52-like genes in cancer tissues may therefore reflect their genomic distributions, with human D52 and D54 genes localising to genomic regions (chromosomes 8q21 and 20q13, respectively) which are frequently gained in many cancer types, and harbour multiple amplification targets. Overexpression of D52

R. Boutros et al. / Biochemical and Biophysical Research Communications 325 (2004) 1115–1121

and possibly D54 may therefore be largely produced by genetic mechanisms targeting a shared D52-like function, such as promoting proliferation. It may be more advantageous for a cancer cell to amplify an oncogene found on the same chromosomal arm as other targets, as opposed to targeting a functionally similar, but comparatively isolated oncogene. However, the differential upregulation of D52-like genes in human cancer may also indicate critical functional differences between D52-like proteins. For example, upregulation of D53 may uniquely promote cellular apoptosis [47], which would not be selected for in tumor initiation or progression.

Perspectives and future directions Adaptor proteins can be viewed as key molecular pieces which lock in and out of many biological puzzles and produce potentially highly varied outputs. Increasing evidence suggests that individual D52-like proteins are also multi-functional and influence numerous cellular processes. Moreover, the multi-functionality of these proteins may be dramatically increased by alternative exon splicing, which is predicted to affect transcripts produced from all D52-like genes identified or predicted to date. To fully understand the functions of this expanding protein family, it will be critical to distinguish isoform-specific functions produced by alternative splicing from core functions shared by multiple isoforms or family members. This will involve significant expansion of functional studies from D52 itself to include other related proteins, studies which are underway in our laboratory [M. Shehata, unpublished results]. This question is also integral to the significance of D52 overexpression in cancer. It is currently unclear whether D52 overexpression in cancer reflects a largely genetic mechanism targeting a shared D52 function, or whether this specifically targets a non-redundant, or even uniquely pathological function through genetic and non-genetic mechanisms alike. Whereas expression of individual D52-like proteins is readily distinguished by antibodies [46] for diagnostic purposes, an understanding of the biological significance of D52 overexpression in cancer, and how this relates to the physiological roles of this and related proteins, would clearly facilitate the specific therapeutic targeting of D52 overexpression. Given the frequency with which D52 is overexpressed in breast, prostate, and ovarian carcinoma alone ([26,27,32], Byrne et al., manuscript submitted), such strategies have the potential of being widely applied.

Acknowledgments Work in the Molecular Oncology laboratory is supported by the National Health and Medical Research

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Council of Australia, the Faculty of Medicine of the University of Sydney, donations to the Oncology Department of the ChildrenÕs Hospital at Westmead, and the Oncology ChildrenÕs Foundation.

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