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)

The human T-cell leukemia virus type I (HTLV-I) has been etiologically associated with the development of the adult T-cell leukemia (ATL) as well as degenerative neurologic syndrome termed tropical spastic paraparesis (TSP). HTLV-I encodes a potent transactivator protein termed Tax that appears to play an important role in the process of T-cell immortalization. Even though the mechanisms by which Tax induces transformation are still unknown, it seems likely that the ability of Tax to alter the expression of many cellular genes plays an important part in this process. Tax does not bind directly to DNA but rather deregulates the activity of cellular transcription factors. One family of host transcription factors whose activity is altered by Tax includes NF-kappa B/Rel. These transcription factors are post-transcriptionally regulated by their assembly with a second family of inhibitory proteins termed I kappa B that serve to sequester the NF-kappa B/Rel complexes in the cytoplasm. Upon cellular activation, I kappa B alpha is phosphorylated, polyubiquitinated, and degraded in the proteasome. This proteolytic event liberates NF-kappa B, permitting its rapid translocation into the nucleus where it binds to its cognate enhancer elements. Similarly, the p105 precursor of the NF-kappa B p50 subunit is also post-translationally processed in the proteasome. The mechanisms by which Tax activates NF-kappa B remain unclear, and findings presented in the literature are often controversial. We identified a physical interaction between Tax and the HsN3 subunit of the human proteasome. This raises the intriguing possibility that physical association of the HsN3 proteasome subunit with HTLV-I Tax coupled with the independent interaction of Tax with either p100 or p65-I kappa B alpha targets these cytoplasmic NF-kappa B/Rel complexes to the proteasome for processing.
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PMID:Interaction of HTLV-I Tax with the human proteasome: implications for NF-kappa B induction. 879 8

The HTLV-1 singly spliced open reading frame I protein, p12(I), is highly unstable and appears to be necessary for persistent infection in rabbits. Here we demonstrate that p12(I) forms dimers through two putative leucine zipper domains and that its stability is augmented by specific proteasome inhibitors. p12(I) is ubiquitylated, and mutations of its unique carboxy-terminus lysine residue to an arginine greatly enhance its stability. Interestingly, analysis of 53 independent HTLV-1 strains revealed that the natural p12(I) alleles found in ex vivo samples of tropical spastic paraparesis-HTLV-1-associated myelopathy patients contain a Lys at position 88 in some cases, whereas arginine is consistently found at position 88 in HTLV-1 strains from all adult T-cell leukemia-lymphoma (ATLL) cases and healthy carriers studied. This apparent segregation of different alleles in tropical spastic paraparesis-HTLV-associated myelopathy and ATLL or healthy carriers may be relevant in vivo, since p12(I) binds the interleukin-2 receptor beta and gammac chains, raising the possibility that the two natural alleles might affect differently the regulation of these molecules.
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PMID:A lysine-to-arginine change found in natural alleles of the human T-cell lymphotropic/leukemia virus type 1 p12(I) protein greatly influences its stability. 1040 Jul 40

HTLV-1 has a complex genome, and contains four open reading frames (ORFs) in the 3' region encoding viral and cellular regulatory proteins. p12 is a small, ORF I-encoded hydrophobic protein, the function of which is not well understood. It has been shown that p12 enhances the E5-transforming ability of bovine papillomavirus; and binds to the 16-kDa subunit of the vacuolar ATPase pump, immature forms of the beta and gamma(c) chains of the interleukin 2 receptor, and the free chain of MHC I. p12 carrying a lysine residue (p12K) at position 88 of its sequence may be rapidly degraded in the cell via proteasome, whereas p12 with an arginine residue (p12R) at the same position is severalfold more stable. These alleles are found in proviral DNA of HTLV-1-infected individuals and it was previously observed that the p12K allele was more frequent in HAM/TSP (HTLV-1-associated myelopathy/tropical spastic paraparesis) patients and was not found at all in asymptomatic carriers, whereas patients with adult T cell leukemia/lymphoma (ATLL) carry the p12R allele. To extend these observations and verify whether the p12K mutation could be used as a marker of progression to HAM/TSP, we analyzed 37 HAM/TSP patients and 40 asymptomatic carriers at different stages of infection. In our cohort, only one HAM/TSP patient carried the p12K phenotype, which accounted for a frequency of 2.7% (1 of 37). We also found, among the 40 asymptomatic HTLV-1 carriers, one who presented the p12K phenotype, contrasting with previous publications. Thus, p12K does not seem to be universally diagnostic for HTLV-1-associated neurological disease. Further screening of HTLV-1-infected individuals in other populations may elucidate this observation.
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PMID:Frequency of p12K and p12R alleles of HTLV Type 1 in HAM/TSP patients and in asymptomatic HTLV type 1 carriers. 1223 Sep 32

Human T-cell leukaemia virus type 1 (HTLV-I), the aetiological agent of adult T-cell leukaemia (ATL) and tropical spastic paraparesis (TSP/HAM), transforms human T-cells in vivo and in vitro. The Tax protein of HTLV-I is essential for cellular transformation as well as viral and cellular gene transactivation. The interaction of Tax with cellular proteins is critical for these functions. We previously isolated and characterized a novel Tax-binding protein, TRX (TAX1BP2), by screening a Jurkat T-cell cDNA library. In the present study, we present evidence that the tumour suppressor p53 targets the TRX protein for proteasome degradation. Pulse-chase experiments revealed that p53 enhanced the degradation of TRX protein and reduced the half-life from 2.0 to 0.25 h. p53 mutants R248W and R273H enhance TRX degradation suggesting a transcriptionally independent mechanism. Both HTLV-I Tax and the proteasome-specific inhibitor MG132 inhibited p53-mediated TRX protein degradation. These results suggest that TRX degradation is mediated through activation of the proteasome protein degradation pathway independent of transcriptional function of p53. Our results provide the first experimental evidence that Tax inhibits transcription-dependent and independent functions of p53.
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PMID:P53 facilitates degradation of human T-cell leukaemia virus type I Tax-binding protein through a proteasome-dependent pathway. 1265 90