Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert anti-proliferative, differentiation-inducing, pro-apoptotic and other biological effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal retinoid biological effects. Direct retinoid targets contain retinoid responsive elements in their promoters, are directly regulated by retinoids and reproduce retinoid biological effects once introduced into a responsive cell context. Through studies conducted in in vitro models, a proteolytic mechanism was linked to retinoid induced tumor cell differentiation and chemopreventive effects. Retinoid treatments can activate the proteasome-dependent degradation pathway. In acute promyelocytic leukemia (APL), all-trans-retinoic acid (RA) can also trigger degradation of the oncogenic protein, PML-RARalpha. Microarray analysis revealed involvement of an E1-like ubiquitin-activating enzyme, UBE1L, in this induction. Retinoid chemopreventive activity in human bronchial epithelial cells was linked to triggering of G(1) cell cycle arrest, concomitant growth suppression, and a decline in expression of G(1) cyclins. This can engage proteasome-dependent cyclin degradation, causing G(1) arrest and this permits repair of genomic DNA damage. The epidermal growth factor receptor (EGFR) was also identified as a retinoid target. Retinoids exert diverse biological effects. Different retinoid target genes likely trigger distinct effects. Identification of target genes is the next step towards a molecular understanding of mechanisms of retinoid response or resistance in cancer therapy and chemoprevention.
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PMID:Retinoid targets in cancer therapy and chemoprevention. 1450 93

HHARI (also known as ARIH1) is an ubiquitin-protein ligase and is the cognate of the E2, UbcH7 (UBE2L3). To establish a functional role for HHARI in cellular proliferation processes, we performed a reverse genetics screen that identified n=86/522 (16.5%) ubiquitin conjugation components that have a statistically significant effect on cell proliferation, which included HHARI as a strong hit. We then produced and validated a panel of specific antibodies that establish HHARI as both a nuclear and cytoplasmic protein that is expressed in all cell types studied. HHARI was expressed at higher levels in nuclei, and co-localized with nuclear bodies including Cajal bodies (p80 coilin, NOPP140), PML and SC35 bodies. We confirmed reduced cellular proliferation after ARIH1 knockdown with individual siRNA duplexes, in addition to significantly increased levels of apoptosis, an increased proportion of cells in G2 phase of the cell cycle, and significant reductions in total cellular RNA levels. In head and neck squamous cell carcinoma biopsies, there are higher levels of HHARI expression associated with increased levels of proliferation, compared to healthy control tissues. We demonstrate that HHARI is associated with cellular proliferation, which may be mediated through its interaction with UbcH7 and modification of proteins in nuclear bodies.
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PMID:Human Homolog of Drosophila Ariadne (HHARI) is a marker of cellular proliferation associated with nuclear bodies. 2305 69