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Aberrant accumulation of b-catenin is closely related to carcinogenesis. Mutations in the p53 gene are reported to induce the aberrant accumulation of b-catenin in the absence of dysfunction in the glycogen synthase kinase 3b (GSK3b)-mediated degradation pathway, but the mechanism remains incompletely understood. Here, we show that human coiled-coil domain containing 85B (CCDC85B) is induced by p53 and regulates b-catenin activity via interaction with the T-cell factor 4 in the nucleus. Moreover, CCDC85B enhances the degradation of b-catenin and suppresses tumor cell growth. In conclusion, we revealed that CCDC85B-induced degradation of b-catenin is independent of GSK3b and other p53-inducible products, Siah-1L, suggesting that CCDC85B constitutes the one of the frameworks of p53-induced multiple regulatory pathways for b-catenin activity.

Human T-cell leukemia virus type 1 (HTLV-1) encodes an antisense viral gene product termed HTLV-1 basic leucine-zipper factor (HBZ). HBZ forms heterodimers with c-Jun, a member of the AP-1 family, and promotes its proteasomal degradation. Although most proteasomal substrates are targeted for degradation via conjugation of polyubiquitin chains, we show that ubiquitination is not required for HBZ-mediated proteasomal degradation of c-Jun. We demonstrate that HBZ directly interacts with both the 26 S proteasome and c-Jun and facilitates the delivery of c-Jun to the proteasome without ubiquitination. HBZ acts as a tethering factor between the 26 S proteasome and its substrate, thereby bypassing the targeting function of ubiquitination. These findings disclose a novel viral strategy to utilize the cellular proteolytic system for viral propagation.Protein degradation plays a variety of roles in fundamental cellular processes, including the cell cycle, apoptosis, immune response, and disposal of misfolded or oxidized proteins (1-3). The ubiquitin-proteasome system has evolved as a key machinery in the selective degradation of intracellular short-lived regulatory or abnormal proteins. Most proteasomal substrates are tagged with polyubiquitin, which serves as a recognition signal for the 26 S proteasome. The cellular machinery that adds ubiquitin to substrates consists of three main enzyme classes. The E1 ubiquitin-activating enzyme transfers activated ubiquitin to the E2 ubiquitin-conjugating enzyme, which, in combination with E3 ubiquitin ligase, transfers ubiquitin to the substrate. The E3 ubiquitin ligase associates with the substrate and confers substrate specificity (3).The proteasome is a major nonlysosomal proteolytic apparatus. The catalytic core of this multisubunit proteolytic complex is the 20 S proteasome. The addition of a 19 S regulatory complex to either or both ends of the 20 S proteasome forms the 26 S proteasome. The 19 S regulatory complex recognizes polyubiquitin chains on substrates and catalyzes deubiquitination, denaturation, and translocation of the unfolded substrate into the 20 S catalytic core for degradation (4). Thus, the substrates for the actual proteolysis are unfolded and nonubiquitinated. Therefore, if a protein can be delivered to the proteasome in a denatured or partially unfolded state, ubiquitination should not be required for its degradation (5, 6). Recently, there have been emerging reports of proteasome-dependent, ubiquitin-independent degradation of eukaryotic proteins (7), including ornithine decarboxylase (ODC) 2 (8), p53 (9), p21 waf1/cip1 (10, 11), and retinoblastoma (Rb) protein (12, 13), suggesting the significance of this alternative pathway for various cellular events. However, the mechanism by which proteasomes recognize nonubiquitinated substrates is not well understood.A variety of viruses are known to utilize the host ubiquitinproteasome system to dysregulate cellular functions for their benefit. Notably, human papillomavirus type-16 E6 protein acts as a part of the ...

HTLV-1 infection causes adult T-cell leukemia (ATL). The development of ATL is thought to be associated with disruption of transcriptional control of cellular genes. HTLV-1 basic leucine-zipper (bZIP) factor, HBZ, is encoded by the complementary strand of the provirus. We previously reported that HBZ interacts with c-Jun and suppresses its transcriptional activity. To identify the cellular factor(s) that interact with HBZ, we conducted a yeast two-hybrid screen using full-length HBZ as bait and identified MafB. HBZ heterodimerizes with MafB via each bZIP domain. Luciferase analysis revealed a significant decrease in transcription through Maf recognition element (MARE) in a manner dependent on the bZIP domain of HBZ. Indeed, production of full-length HBZ in cells decreased the MARE-bound MafB protein, indicating that HBZ abrogates the DNA-binding activity of MafB. In addition, HBZ reduced the steady-state levels of MafB, and the levels were restored by treatment with a proteasome inhibitor. These results suggest a suppressive effect of HBZ on Maf function, which may have a significant role in HTLV-1 related pathogenesis.