Multiple Forms of Proteasomes and their Role in Tumor Fate

Abstract

Mammalian and human cells contain multiple forms of proteasomes different in their structure and functions. 26S-proteasome pool regulates most cellular processes through ATP-and ubiquitin-dependent hydrolysis of proteins participating in these processes. This function is possible due to 19S-subparticle capable to recognize ubiquitinated proteins, unfold and direct them into the proteolytic chamber. 20S-proteasome pool is capable to degrade some damaged and foreign proteins in an ATP-and ubiquitin-independent manner. Among both proteasome pools, the immune proteasomes effectively produce antigen epitopes for MHC class I molecules and play a crucial role in the antitumor immunity. Excluding the immune proteasomes from their cells, numerous tumors avoid the immune system. On the contrary, tumor cells enhance the expression of the housekeeping proteasomes and 19S-subparticle.At this time, bortezomib, a patented proteasome inhibitor, is used as an anticancer therapy. This drug induces the cell cycle arrest and apoptosis of dividing tumor cells. However, bortezomib causes, firstly, deviations in immune functions, secondly, the increase of the housekeeping proteasome expression by a feedback mechanism. Taking into account the recent patents, we consider prospects of the development of new drugs directed to the regulation of the expression of the immune and housekeeping proteasomes and 19S-subparticle in tumor cells.

Changes in proteasome pool in human papillary thyroid carcinoma development

“…The discovery of the protein hydrolysis system in the 1980s involving proteasomes and touching all cellular processes provided a new impulse to the studies in this area. Proteasomes, multisubunit multiproteinase complexes, are present in mammalian cells in multiple forms with different structures and physiological functions [1][2][3][4]. Depending on the nature of the protease subunits, proteasomes can be divided into two groups, the constitutive and immune proteasomes.…”

“…Both constitutive and immune proteasomes form pools of the 26S-and 20S proteasomes [3]. Overall, the 26S proteasome pool may be indicated as 19S-20S + 19S-20S-19S + 19S-20S-Reg, where 20S is the core proteolytic particle; 19S is the activator responsible for binding to ubiquitinated target proteins, unfolding and directing them into the proteolytic chamber; Reg is one of the different regulator proteins (PA28, PA200, PI31).…”

Changes in the proteasome function after induction of donor-specific tolerance in rats with ovarian allograft

“…Proteasomes are intracellular high molecular weight protein complexes for selective protein degradation (Arrigo et al, 1988). In turn, immune proteasomes are involved in formation of the antigenic epitopes capa ble of binding to major histocompatibility complex class I molecules and play a key role in the T cellmediated immune response (Rock and Goldberg, 1999;Sharova and Zakharova, 2008). Bortezomib, an inhibitor of proteasome activity, is used in transplan tology as an immunosuppressant (Everly et al, 2009), which suggests that it is feasible to regulate the immune response to graft via modification of the pro teasome pool.…”

Diagnostics of thyroid cancer: Limitations of the existing methods and perspectives for future developments

“…Proteasomes are organized so that their pro teolytically active centers are turned inside the pro teolytic chamber so as to prevent accidental protein cleavage. All eukaryotic cells contain multiple forms of proteasomes that differ from one another in the struc ture and specificity of protein hydrolysis (Sharova and Zakharova, 2008). The smallest functional unit, 20S proteasome, is a cylindrical structure with the length 15-17 nm and 11-12 nm diameter, which consists of two inner and two outer rings (Groll et al, 1997;Sharova and Zakharova, 2008).…”

“…All eukaryotic cells contain multiple forms of proteasomes that differ from one another in the struc ture and specificity of protein hydrolysis (Sharova and Zakharova, 2008). The smallest functional unit, 20S proteasome, is a cylindrical structure with the length 15-17 nm and 11-12 nm diameter, which consists of two inner and two outer rings (Groll et al, 1997;Sharova and Zakharova, 2008). In eukaryotes each of the two inner rings is formed by seven different β sub units surrounding the hollow in which proteolysis takes place.…”