Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitin-mediated proteolysis plays a critical role in the degradation of proteins important in the cellular processes, such as cell cycle/division, differentiation and development, DNA repair, transcriptional regulation, and signaling. It is carried out by a complex cascade of enzymes that contain a high degree of specificity to motifs found in many proteins with rapid turnover. For example, the PEST motifs are hydrophilic stretches of amino acids that serve as signals for proteolytic degradation. In this study, we propose that amino acid altering non-synonymous single nucleotide polymorphisms (nsSNP) result in the abolishment or creation of putative PEST motifs, and thus lead to abnormal stabilization or degradation of the proteins. Using a web-based algorithm, PESTFind, we analyzed a total of 253 nsSNPs from proteins involved in cell cycle (n = 24), DNA repair (n = 128), and TGFbeta signaling pathway (n = 101). Fifteen nsSNPs were located within putative PEST sequences, and 9/15 (60%) either created or abolished these PEST motifs. PEST motifs were abolished in the presence of nsSNPs in CCND3, PMS2, POLE4, SITPEC, and PPARG and putative PEST motifs were created in NEIL2, BIRC4, MLL2, and PPP1R15A. Although experimental analyses are required to confirm these results, they suggest that nsSNPs can induce changes in ubiquitin-mediated protein degradation.
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PMID:Human non-synonymous single nucleotide polymorphisms can influence ubiquitin-mediated protein degradation. 1759 38

Epigenetic silencing of tumor suppressor genes (TSGs) through DNA methylation and histone changes is a main hallmark of cancer. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a potent oncogene overexpressed in various solid and haematological tumors and its high expression levels are associated with decreased expression of several TSGs including p16 INK4A , BRCA1, PPARG and KiSS1. Using its several functional domains, UHRF1 creates a strong coordinated dialogue between DNA methylation and histone post-translation modification changes causing the epigenetic silencing of TSGs which allows cancer cells to escape apoptosis. To ensure the silencing of TSGs during cell division, UHRF1 recruits several enzymes including histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1) and histone lysine methyltransferases G9a and Suv39H1 to the right place at the right moment. Several in vitro and in vivo works have reported the direct implication of the epigenetic player UHRF1 in tumorigenesis through the repression of TSGs expression and suggested UHRF1 as a promising target for cancer treatment. This review describes the molecular mechanisms underlying UHRF1 regulation in cancer and discusses its importance as a therapeutic target to induce the reactivation of TSGs and subsequent apoptosis.
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PMID:Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer. 2783 16