Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

STRA13 is a hypoxia-inducible bHLH transcription factor implicated in the pVHL/HIF, TGF-beta, and Jak/STAT pathways. To further characterize the STRA13 protein-interacting network and mechanisms of STRA13-dependent transcription, we utilized yeast two-hybrid screening. Here we report on STRA13 interaction with the cell cycle-associated transcription factor MSP58. We demonstrated that the basic domain of STRA13 and the FHA domain of MSP58 are essential for this association. We performed phospho-peptide mapping of both MSP58 and STRA13 and showed that their association was modulated by the STRA13 phosphorylation status. STRA13/MSP58 complex formation protected both proteins from the proteasome-mediated degradation, extending their half-lives considerably. STRA13 and MSP58 synergistically co-operated in the STRA13 promoter-driven transcription repression. Both proteins were co-localized in the nucleus and showed transcript accumulation during the S phase of the cell cycle. Thus, we characterize a novel STRA13-associated transcription repression complex and provide a link between cell cycle regulation and STRA13 activity.
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PMID:Association, mutual stabilization, and transcriptional activity of the STRA13 and MSP58 proteins. 1571 73

Checkpoint with FHA and RING finger domains (CHFR) was first recognized as an early mitotic checkpoint protein that delayed the cell cycle in response to microtubule-targeting drugs. It is an E3 ubiquitin ligase that ubiquitinates target proteins to direct them to the proteasome for degradation or to alter their activity. To date, however, the downstream target proteins critical to CHFR's normal cellular functions largely remain unidentified with the exception of the key mitosis regulators, and oncogenes, PLK1 and Aurora A kinases. Rapidly growing evidence in mice, primary human tumors, and mammalian cell culture models indicate that CHFR may also function as a potent tumor suppressor. Interestingly, studies reported to date suggest that CHFR both controls a novel prophase checkpoint early in mitosis and regulates chromosome segregation later in mitosis to maintain genomic stability. In addition, loss of CHFR sensitizes cancer cells to microtubule poisons, altering chemoresponsiveness to taxanes and making it a potential biomarker for chemotherapeutic response. Importantly, CHFR may be one of the few proteins that are required for regulating the cell cycle and maintaining genomic instability to inhibit tumorigenesis.
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PMID:CHFR: A Novel Mitotic Checkpoint Protein and Regulator of Tumorigenesis. 1863 60

Chfr, a checkpoint with FHA and RING finger domains, plays an important role in cell cycle progression and tumor suppression. Chfr possesses the E3 ubiquitin ligase activity and stimulates the formation of polyubiquitin chains by Ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins, including Plk1 and Aurora A. While Chfr is a nuclear protein that functions within the cell nucleus, how Chfr is localized in the nucleus has not been clearly demonstrated. Here, we show that nuclear localization of Chfr is mediated by nuclear localization signal (NLS) sequences. To reveal the signal sequences responsible for nuclear localization, a short lysine-rich stretch (KKK) at amino acid residues 257-259 was replaced with alanine, which completely abolished nuclear localization. Moreover, we show that nuclear localization of Chfr is essential for its checkpoint function but not for its stability. Thus, our results suggest that NLS-mediated nuclear localization of Chfr leads to its accumulation within the nucleus, which may be important in the regulation of Chfr activation and Chfr-mediated cellular processes, including cell cycle progression and tumor suppression.
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PMID:Nuclear localization of Chfr is crucial for its checkpoint function. 1932 84