JADE1

A small family of proteins named Gene for Apoptosis and Differentiation (JADE) includes three members encoded by individual genes: Plant Homeo-domain-17 (PHF17, JADE1), PHF16 (JADE3), and PHF15 (JADE2). All JADE family proteins bear two notable mid molecule domains: the canonical Plant Homeo-domain (PHD) zinc finger and extended PHD-like zinc finger. JADE1 therefore is classified as a member of the PHD protein family. There are two known protein products of the PHF17 gene, the full length JADE1 (JADE1L) and its splice variant missing the C-terminal fragment also called short isoform (JADE1S). == Discovery ==

Nagase et al. cloned and sequenced 100 individual cDNAs from fetal brain cDNA library, including clone KIAA1807 which was designated PHF17. Based on sequence database analysis the study suggested that PHF17 may function in nucleic acid managing pathway. JADE1 has been mapped to chromosome 4 (4q26-q27). JADE1 is conserved and its orthologues have been found or predicted in most every metazoan. Gene structure and sequences, variants, conservation, orthologues and paralogs, JADE1 phylogenetic tree and large scale screening of JADE1 tissue expression can be found in several extensive databases (https://www.genecards.org; http://useast.ensembl.org). == Structure ==

The full length JADE1 polypeptide bears one canonical and one extended PHD zinc finger domain. Other domains include the N-terminal candidate PEST domain, enhancer of polycomb-like domain and the C-terminal nuclear localization (NLS) signal Six amino acid residues were identified to be phosphorylated in cell cycle-dependent manner via Aurora A kinase pathway. JADE1 is a target of phosphorylation by Casein kinase 2 (CK2). In addition, multiple phosphorylation sites are found by high throughput screening approaches and in silico analysis. Summary schematic for JADE1L and JADE1S protein phosphorylation sites with references is found in. The crystal structure of JADE1 PHD domains has not been solved. Canonical PHD finger motif has signature C4HC3, represents relatively small, stable structure, and is distinct from the C3HC4 type RING finger. PHD domains are able to recognize and bind specific methylated lysine of histone H3, which defines these domains as epigenetic histone code readers. Reviews describing structure and properties of PHD fingers in depth are available. == Cellular function ==

JADE1 proteins are multifunctional and interact with several protein partners. Histone acetylation Function of JADE1 in histone acetylation and transcription activation which required the second extended PHD zinc finger was reported in 2004(16). JADE1 dramatically increases levels of acetylated histone H4 within chromatin, but not histone H3, a specificity characteristic to the MYST family HAT TIP60 and HBO1. TIP60 physically associates with JADE1 and augments JADE1 HAT function in live cells. TIP60 and JADE1 mutually stabilized each other. Transcriptional and HAT activities of JADE1 require PHD2. Results suggest the chromatin targeting role for JADE1 PHD2. In addition, PHD2 of JADE1 binds the N-terminal tail of histone H3 within chromatin context irrespective of methylation status. Studies analyzing native complexes of INhibitor of Growth (ING) PHD finger family of proteins revealed that ING4 and ING5 proteins are associated with JADE1S and HAT HBO1, while ING3 is associated with EPC1 (JADE1 homolog), TIP60 (HBO1 homolog) and several other partners. Both complexes also included a small Eaf6 protein. The biochemical and in silico analysis of complexes formed by HBO1 and TIP60 suggested common architecture and supported the role for JADE1 in bulk histone H4 acetylation. Characterization of JADE1 and HBO1 functional interactions show structural and functional similarities between the complexes(16, 19). Similarly to TIP60, JADE1 and HBO1 mutually stabilize each other. JADE1 binds to and enables HBO1 to enhance global histone H4 acetylation, which requires intact PHD2 finger. Several potential transcription targets of JADE1 have been suggested from experiments using screening approaches. According to screening genomic analysis done by ChIP-chip assay JADE1L complex is found mainly along the coding regions of many genes and JADE1L abundance correlates mostly with H3K36me3 histone mark. JADE1L over expression correlates with increased quantities of H4acK8 in the coding region of many genes. JADE1 isoforms assemble at least two different complexes, JADE1L-HBO1-ING4/5 and JADE1S-HBO1 complex. Several studies support cell cycle role for JADE1 linked to HBO1 pathway. The effects of JADE1 depletion on DNA replication events are similar to those described originally for HBO1 and suggests adaptor role for JADE1 in HBO1-mediated cell cycle regulation. JADE1 role in DNA damage has been suggested. A recently discovered non-coding RNA lncRNA-JADE regulates JADE1 expression and provides a functional link between the DNA damage response (DDR) and bulk histone H4 acetylation. Results support role in DNA synthesis linked to histone H4 acetylation. Upon completion of mitosis around telophase, the main pool of the JADE1S protein undergoes de-phosphorylation and re-associates with apparently condensing chromatin inside the reformed nuclei. Cytokinesis is the final step of cell cycle which controls fidelity of division of cellular content, including cytoplasm, membrane, and chromatin. Cytokinetic bridge is severed during the final abscission which occurs near the midbody and may take up to 2 hours. Cytokinesis and final abscission are tightly controlled by regulatory protein complexes and checkpoint proteins. The number of reports concerning cytokinesis control has been growing over the past decade. JADE1 role in cytokinesis was demonstrated by use of several functional assays and cell culture models. pVHL The first protein partner of JADE1S has been identified in 2002 in a study searching for new partners of the pVHL, which is a tumor suppressor. The human pVHL is mutated in von Hippel–Lindau hereditary disease, and in majority of sporadic clear cell renal carcinomas. Properties and function of pVHL have been investigated for many decades and extensive literature is available. One of the better known functions of pVHL is to mediate protein ubiquitination and proteosomal degradation. As a component of ubiquitin ligase E3 complex pVHL binds and targets several known factors, including HIF1a and HIF2a for ubiquitination. The VHL protein has been intensely studied and the link of naturally occurring mutations to cancers established. Other causative HIF-1a-independent pVHL pathways have been considered. The pVHL-JADE1S physical interaction was identified by yeast-two hybrid screening analysis and was further confirmed biochemically. Co-transfection of pVHL increased JADE1S protein half-life and abundance, suggesting potential positive relationship. Certain pVHL cancer-derived truncations but not point mutations diminished pVHL-JADE1 stabilization function, suggesting link to pVHL-associated cancers. Molecular pathways and cellular significance of JADE1-pVHL interactions are not well understood. Single study describing JADE1S intrinsic ubiquitin-ligase activity and ubiquitination of beta-catenin has been reported in year 2008. Based on that study a model has been proposed that pVHL regulates beta-catenin through JADE1, and PHD zinc fingers are required for this activity. Apoptosis JADE1S function in apoptosis has been proposed but the mechanisms remain elusive and results are hard to reconcile. According to studies, JADE1 overexpression slows rates of cellular growth and induces cell cycle arrest protein p21. Several attempts to establish dependable cell lines stably expressing JADE1S protein have not been successful, presumably due to the negative cells self-selection. Contrary to that, another study shows that JADE1 downregulation decreased rates of DNA synthesis in synchronously dividing cells. According to indirect immunofluorescence and microscopy analysis of cultured cells, cultured cells overload with JADE1 protein causes cell toxicity and side effects. Cells undergo morphological changes that do not resemble apoptosis but suggest severely impaired cell cycle including dyeing cells with abnormal shapes and large, multi-lobular nuclei. Based on JADE1S-mediated regulation of cell cycle other interpretations are considered: JADE1 overload might cause prolonged NoCut and stalled cytokinesis or severe cell cycle misbalance rather than direct transcription activation of apoptosis. == Biological role ==

The biological role of JADE1 has not been elucidated. Limited number of publications addresses this question using mice models. The most comprehensive study which was published in 2003, identified mice orthologue of human JADE1, Jade1, and investigated Jade1 expression during mice embryogenesis. Role of JADE1 in epithelial cell proliferation was addressed in a murine model of acute kidney injury and regeneration. Expression patterns and dynamics of HBO1-JADE1S/L were examined in regenerating tubular epithelial cells. Ischemia and reperfusion injury resulted in an initial decrease in JADE1S, JADE1L, and HBO1 protein levels, which returned to the baseline during renal recovery. Expression levels of HBO1 and JADE1S recovered as cell proliferation rate reached maximum, whereas JADE1L recovered after bulk proliferation had diminished. The temporal expression of JADE1 correlated with the acetylation of histone H4 (H4K5 and H4K12) but not that of histone H3 (H4K14), suggesting that the JADE1-HBO1 complex specifically marks H4 during epithelial cell proliferation. The results of the study implicate JADE1-HBO1 complex in acute kidney injury and suggest distinct roles for JADE1 isoforms during epithelial cell recovery. == Disease associations ==

Role of JADE1 in human disease has not been elucidated. A recent study searched for novel submicroscopic genetic changes in myelofibrosis, which is a bone marrow cancer. The study identified seven novel deletions and translocations in small cohort of patients with primary myelofibrosis. JADE1 and the adjacent gene called Sodium channel and clathrin linker 1 (SCLT1) were significantly modified. As a result of mutation, JADE1 gene has deletions of intron 5-6 and exons 6–11, which would produce JADE1 missing a large chunk of protein starting from the PHD zinc finger. The relevance to pathogenesis is under investigation. In a handful of pilot studies JADE1 expression was examined in colon cancers and renal carcinomas. The results in these studies do not always reconcile. The results of some studies are generated mostly from the histochemical analysis of tumor specimens using JADE1 antibody with uncharacterized specificities towards JADE1 in general, and JADE1S or JADE1L in particular. Results of study using in silico microarray algorithm analysis shows, that PHF17 mRNA may play a role in the development of pancreatic cancer. These promising lines of investigations require further controls and additional assessments. Recent evidence suggests that JADE1 may play a role in neurodegenerative tauopathies. . Specifically, the JADE1 locus was identified in a small autopsy-based genome-wide association study in subjects with primary-age related tauopathy (PART). Further histological and biochemical studies showed a specific interaction between JADE1 and isoforms of the microtubule-associated protein tau with four microtubule binding domains, but not those with three. In vivo Drosophila models showed that knock-down of the fly ortholog rhinoceros exacerbated tau toxicity related phenotypes suggesting a protective role. Histological studies showed that JADE1 accumulates in most tauopathies, with the exception of Pick's disease, which is notable because it is differentiated by the selective accumulation of tau isoforms with three microtubule binding domain repeats, which JADE1 has low affinity for. Further studies are required to understand the role of JADE1 in neurodegeneration. == Interactions ==

Several proteins interact with JADE1, including: MAPT, pVHL, TIP60, HBO1, ING4, ING5, β-catenin, NPHP4. ==Notes==