A proteolytic system that compensates for loss of proteasome function. Nature

Center for Cancer Research, Department for Biology, Massachusetts Institute of Technology, Cambridge 02139-4307, USA.
Nature (Impact Factor: 41.46). 05/1998; 392(6676):618-22. DOI: 10.1038/33443
Source: PubMed


Proteolysis is essential for the execution of many cellular functions. These include removal of incorrectly folded or damaged proteins, the activation of transcription factors, the ordered degradation of proteins involved in cell cycle control, and the generation of peptides destined for presentation by class I molecules of the major histocompatibility complex. A multisubunit protease complex, the proteasome, accomplishes these tasks. Here we show that in mammalian cells inactivation of the proteasome by covalent inhibitors allows the outgrowth of inhibitor-resistant cells. The growth of such adapted cells is apparently maintained by the induction of other proteolytic systems that compensate for the loss of proteasomal activity.

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Available from: Maria Gaczynska, Feb 06, 2015
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    • "TPPII is able to protect cells under conditions of cellular stress. For example, it is up-regulated in lymphoma cells adapted to grow in the presence of proteasome inhibitors [18], [20], [21]. TPPII also plays a critical role in several vital cellular processes such as antigen processing, apoptosis, DNA damage repair, or cell division, and is also involved in muscle wasting, obesity, and cancer [22], [23]. "
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    ABSTRACT: Recent studies have identified Ca(2+) stores in sperm cells; however, it is not clear whether these Ca(2+) stores are functional and how they are mobilized. Here, in vitro and in vivo, we determined that tripeptidyl peptidase II antagonists strongly activated the cAMP/PKA signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation. We demonstrated that in the absence of Ca(2+), TPIII antagonists elevated the intracellular Ca(2+) levels in sperm, resulting in a marked improvement in sperm movement, capacitation, acrosome reaction, and the in vitro fertilizing ability. This antagonist-induced release of intracellular Ca(2+) could be blocked by the inhibitors of ryanodine receptors (RyRs) which are the main intracellular Ca(2+) channels responsible for releasing stored Ca(2+). Consistent with these results, indirect immunofluorescence assay using anti-RyR antibodies further validated the presence of RyR3 in the acrosomal region of mature sperm. Thus, TPPII can regulate sperm maturation by modulating intracellular Ca(2+) stores via the type 3 RyR.
    PLoS ONE 06/2013; 8(6):e66634. DOI:10.1371/journal.pone.0066634 · 3.23 Impact Factor
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    • "TPPII is also upregulated in tumor cells, a finding that might have an impact on cancer therapy: EL4 thymoma or EL4 lymphoma cells adapted to proteasome-inhibition as well as Burkitt's lymphoma cells, where the proteasome appears to be functionally impaired, show increased TPPII activity [15] [36] [37]. From such observations it was concluded that TPPII may allow survival of these cells by compensating for a loss of proteasome function [15] [36]. Indeed, it was shown that in Burkitt's lymphoma cells, protein turnover is unaffected and that ubiquitinated proteins do not accumulate [37] unless the cells are treated with the covalent serine protease inhibitor AAF-CMK, which inhibits TPPII [37] [38]. "
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    ABSTRACT: Tripeptidyl peptidase II is the largest known eukaryotic peptidase. It has been described as a multi-purpose peptidase, which, in addition to its house-keeping function in intracellular protein degradation, plays a role in several vital cellular processes such as antigen processing, apoptosis, or cell division, and is involved in diseases like muscle wasting, obesity, and in cancer. Biochemical studies and bioinformatics have identified TPPII as a subtilase, but its structure is very unusual: it forms a large homooligomeric complex (6 MDa) with a spindle-like shape. Recently, the high-resolution structure of TPPII homodimers (300 kDa) was solved and a hybrid structure of the holocomplex built of 20 dimers was obtained by docking it into the EM-density. Here, we summarize our current knowledge about TPPII with a focus on structural aspects. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
    Biochimica et Biophysica Acta 07/2011; 1824(1):237-45. DOI:10.1016/j.bbapap.2011.07.002 · 4.66 Impact Factor
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    • "Chymotryptic, tryptic, and caspase proteasome activities were measured as described previously [25] with a few minor modifications. A549, H1299 and their primary lung tumor sphere cells were washed with phosphate buffered saline (PBS) and pelleted by centrifugation. "
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    PLoS ONE 10/2010; 5(10):e13298. DOI:10.1371/journal.pone.0013298 · 3.23 Impact Factor
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