Cellular function JADE1

1 cellular function

1.1 histone acetylation
1.2 cell cycle
1.3 pvhl
1.4 apoptosis

cellular function

jade1 proteins multifunctional , interact several protein partners.

histone acetylation

function of jade1 in histone acetylation , transcription activation required second extended phd zinc finger reported in 2004(16). jade1 dramatically increases levels of acetylated histone h4 within chromatin, not histone h3, specificity characteristic myst family hat tip60 , hbo1. tip60 physically associates jade1 , augments jade1 hat function in live cells. tip60 , jade1 mutually stabilized each other. transcriptional , hat activities of jade1 require phd2. results suggest chromatin targeting role jade1 phd2. in addition, phd2 of jade1 binds 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 ing4 , ing5 proteins associated jade1s , hat hbo1, while ing3 associated epc1 (jade1 homolog), tip60 (hbo1 homolog) , several other partners. both complexes included small eaf6 protein. biochemical , in silico analysis of complexes formed hbo1 , tip60 suggested common architecture , supported role jade1 in bulk histone h4 acetylation. characterization of jade1 , hbo1 functional interactions show structural , functional similarities between complexes(16, 19). tip60, jade1 , hbo1 mutually stabilize each other. jade1 binds , enables hbo1 enhance global histone h4 acetylation, requires intact phd2 finger. hbo1, jade1 responsible bulk histone h4 acetylation in cultured cells. h4k5, h4k12, , h4k8 targets of jade1-dependent acetylation in cultured cells , in vivo. several potential transcription targets of jade1 have been suggested experiments using screening approaches. according screening genomic analysis done chip-chip assay jade1l complex found along coding regions of many genes , jade1l abundance correlates h3k36me3 histone mark. jade1l on expression correlates increased quantities of h4ack8 in coding region of many genes. 2 phd zinc fingers of jade1 appear bind preferentially non-methylated n-terminal peptide of histone. jade1 isoforms assemble @ least 2 different complexes, jade1l-hbo1-ing4/5 , jade1s-hbo1 complex. due lack of c-terminal fragment, jade1s incapable of binding ing4/5 partners. small less characterized protein eaf6 component of jade1 complexes.

cell cycle

acetylation of n-terminal fragments of bulk histone h4 has been known correlate dna synthesis , cell division. several studies support cell cycle role jade1 linked hbo1 pathway. both, jade1 , hbo1 independently required acetylation of bulk histone h4 in cultured cells. depletion of jade1 proteins sirna results in 1) decreased levels of histone h4 bulk acetylation; 2) slower rates of dna synthesis in cultured cells; 3) decreased levels of total , chromatin-bound hbo1; 4) abrogation of chromatin recruitment of mcm7. agreeing these results, jade1l over-expression increases chromatin-bound mcm3 protein. effects of jade1 depletion on dna replication events similar described hbo1 , suggests adaptor role jade1 in hbo1-mediated cell cycle regulation.

jade1 role in dna damage has been suggested. discovered non-coding rna lncrna-jade regulates jade1 expression , provides functional link between dna damage response (ddr) , bulk histone h4 acetylation. results support role in dna synthesis linked histone h4 acetylation. in cultured cells knock down of lncrna-jade increased cells sensitivity dna damaging drugs. in mice tumor xenograft model, knock down of lncrna-jade inhibited xenograft mammary tumor growth. in pilot human study, higher levels of lncrna-jade jade1 protein detected in breast cancer tissues compared normal tissues. lastly, higher levels of jade1 protein inversely correlated survival rates of patients breast cancer. study suggests lncrna-jade might contribute breast tumorigenesis, , jade1 protein mediates @ least part of effect. jade1 , cytokinesis. jade1s negatively regulates cytokinesis of epithelial cell cycle, function specific small isoform. first report suggested jade1 function in g2/m/g1 transition showed during late g2 phase, jade1s undergoes phosphorylation linked dissociation chromatin cytoplasm. mass spectral analysis identified total of 6 individual amino acid residues phosphorylated mitotic kinase. based on pharmacological analysis, jade1 phosphorylation , compartmentalization regulated aurora , aurora b pathways. other kinases have been reported , may play role. upon completion of mitosis around telophase, main pool of jade1s protein undergoes de-phosphorylation , re-associates apparently condensing chromatin inside reformed nuclei. discrete pool of jade1s associates cleavage furrow , subsequently appears in midbody of cytokinetic bridge. interestingly, jade1s, not jade1l or hbo1 found in midbody of cells undergoing cytokinesis. spatial regulation of jade1s during cell division suggested role in g2/m g1 transition, includes cytokinesis , final abscission. cytokinesis final step of cell cycle controls fidelity of division of cellular content, including cytoplasm, membrane, , chromatin. cytokinetic bridge severed during final abscission occurs near midbody , may take 2 hours. cytokinesis , final abscission tightly controlled regulatory protein complexes , checkpoint proteins. number of reports concerning cytokinesis control has been growing on past decade.

jade1 role in cytokinesis demonstrated use of several functional assays , cell culture models. dna profiling facs showed jade1s depletion facilitated rates of g1-cells accumulation in synchronously dividing hela cells. depletion of jade1s protein in asynchronously dividing cells decreased proportion of cytokinetic cells, , increased proportion of multi-nuclear cells. data demonstrated jade1 negatively controls cytokinesis, presumably contributing cytokinesis delay. jade1 down-regulation increased number of multi-nuclear cells indicative of failed cytokinesis, while jade1s moderate overexpression augmented number of cytokinetic cells indicative of cytokinetic delay. inhibition of aurora b kinase specific small molecule drugs resulted in release of jade1s-mediated cytokinetic delay , allowed progression of abscission. since aurora b key regulator of nocut, jade1s regulate cytokinesis @ abscission checkpoint control. jade1s not jade1l or hbo1 found in centrosomes of dividing cells throughout cell cycle, , neither of these proteins found in cilia. in contrast, study reported jade1 localization cilia , centrosome. study did not communicate on jade1 isoform specificity. centrosomes cytoskeleton nucleation centers. centrosome signaling contributes definition of cell shape, motility, orientation, polarity, division plane , fidelity of sister chromosome separation during mitosis , cytokinesis.

pvhl

the first protein partner of jade1s has been identified in 2002 in study searching new partners of pvhl, tumor suppressor. few follow studies characterized binding , provided insights on functional interactions of jade1-pvhl. human pvhl mutated in von hippel–lindau hereditary disease, , in majority of sporadic clear cell renal carcinomas. properties , function of pvhl have been investigated many decades , extensive literature available. 1 of better known functions of pvhl mediate protein ubiquitination , proteosomal degradation. component of ubiquitin ligase e3 complex pvhl binds , targets several known factors, including hif1a , hif2a ubiquitination. mechanism of hif1a activation hypoxia , role of pvhl in pathway has been reported on decade ago. vhl protein has been intensely studied , link of naturally occurring mutations cancers established. other causative hif-1a-independent pvhl pathways have been considered. pvhl-jade1s physical interaction identified yeast-two hybrid screening analysis , further confirmed biochemically. co-transfection of pvhl increased jade1s protein half-life , abundance, suggesting potential positive relationship. pvhl cancer-derived truncations not point mutations diminished pvhl-jade1 stabilization function, suggesting link pvhl-associated cancers. molecular pathways , cellular significance of jade1-pvhl interactions not understood. single study describing jade1s intrinsic ubiquitin-ligase activity , ubiquitination of beta-catenin has been reported in year 2008. based on study model has been proposed pvhl regulates beta-catenin through jade1, , phd zinc fingers required activity.

apoptosis

jade1s function in apoptosis has been proposed mechanisms remain elusive , results hard reconcile. according studies, jade1 overexpression slows rates of cellular growth , induces cell cycle arrest protein p21. several attempts establish dependable cell lines stably expressing jade1s protein have not been successful, presumably due negative cells self-selection. contrary that, study shows jade1 downregulation decreased rates of dna synthesis in synchronously dividing cells. according indirect immunofluorescence , microscopy analysis of cultured cells, cultured cells overload jade1 protein causes cell toxicity , side effects. cells undergo morphological changes not resemble apoptosis suggest severely impaired cell cycle including dyeing cells abnormal shapes , large, multi-lobular nuclei. based on jade1s-mediated regulation of cell cycle other interpretations considered: jade1 overload might cause prolonged nocut , stalled cytokinesis or severe cell cycle misbalance rather direct transcription activation of apoptosis.