2.6. Overexpression of PA28<sup>γ</sup> in cancer

Several authors showed the association of PA28γ with tumorigenic pathways and correlation of expression with malignancy and metastasis. In skin carcinogenesis, PA28γ is involved in modulating WNT signaling [54]. The improved survival properties of PA28γ overexpressing cells [46] and the well-documented overexpression in tumors and cancer cell lines raise the question, how PSME3 gene expression is regulated on the transcriptional and translational level.

mice [61]. Noteworthy, aforementioned CDKIs had measurable slow rates of proteasomedependent turnover after depletion of PA28γ, indicating that PA28γ-20S proteasome UIPP is more efficient than the PA28γ-independent pathway. Furthermore, inhibition of aminoterminal ubiquitination via acetylation or mutagenesis of internal lysine residues did not impair degradation of p21 [62]. Degradation of the three mentioned CDKIs could be

Figure 1. Mechanistic diversity of PA28γ-mediated protein turnover. (A) Typical protease complexes and substrates of UIPP. (B) Core components of UPS. Note, that UIPP and UPS are connected by cross talk: 11S and 19S regulators compete for binding to the 20S core protease. Increased assembly of PA28γ complexes is supposed to reduce the relative amount of 30S proteasomes. In cells overexpressing PA28γ, certain proteasomal substrates of PA28γ-20S proteasomes may be recognized by increased turnover, while others may accumulate due to UPS inhibition. The second mode of cross talk takes place, if UIPP degrades E3 enzymes or components required for their activation. As the third mode, PA28γ might increase PPI between E3s (Mdm2) and their substrates (S1, p53), thereby increasing UPS-dependent substrate turnover.

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PA28γ-mediated effects can be assigned mechanistically to distinct categories (Figure 1). Firstly, central to its role in UIPP, PA28γ recruits substrates for degradation by the 20S proteasome. CDKIs revealing features of intrinsically unstructured proteins (IUP) are prototypic for this

Secondly, a cross talk between UIPP and UPS is established, since 11S and 19S regulators compete for binding to 20S proteasomes. Interestingly, overexpression of PA28γ correlates with the increase of some UPS substrates such as c-Myc [63], ERα [58], BclXL, or MART-1 [46]. Such stabilization may indicate inhibitory effects on specific E3 enzymes, UIPP degradation of auxiliary UPS factors, or reduction of the active 30S proteasome pool. Perhaps, putative 30S substrates may escape UPS degradation due to activation of DUBs. Thirdly, UPS-mediated degradation might be affected either by degradation of specific E3 enzymes (Smurf1; [64, 65]) or by enhancing the interaction of specific E3s with their substrates, as has recently been

Here, PA28γ promotes the interaction of p53 and Mdm2 (Figure 1B), thereby reducing total p53 levels in UV-C-radiated cells via the ubiquitin-dependent proteasomal degradation pathway.

performed by 20S proteasomes, but not by 30S proteasomes in vitro [61].

mode [61].

shown for Mdm2:p53:PA28γ [66].

PA28γ-mediated mechanisms supporting cell survival in cancer cells are of high relevance for cancer therapy, particularly in the light of profoundly increased levels of PA28γ in cancer cell lines and in tumor tissue. Highly increased steady-state level of PA28γ was observed majorly in epithelial and mesenchymal tumors such as thyroid neoplasm [55]; breast tumors, particularly those with poor prognosis [56–58]; colorectal cancers [48]; hepatocellular carcinoma [59]; and oral squamous cell carcinoma (OSCC) [60].
