The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of cMyc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of cMyc was also apparent in mouse Fbw7 À/À embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.

The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3-6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.

The cyclin-dependent kinase inhibitor p27(Kip1) is degraded at the G0-G1 transition of the cell cycle by the ubiquitin-proteasome pathway. Although the nuclear ubiquitin ligase (E3) SCF(Skp2) is implicated in p27(Kip1) degradation, proteolysis of p27(Kip1) at the G0-G1 transition proceeds normally in Skp2(-/-) cells. Moreover, p27(Kip1) is exported from the nucleus to the cytoplasm at G0-G1 (refs 9-11). These data suggest the existence of a Skp2-independent pathway for the degradation of p27(Kip1) at G1 phase. We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation. The nuclear export of p27(Kip1) by CRM1 seems to be necessary for KPC-mediated proteolysis. Depletion of KPC1 by RNA interference also inhibited p27(Kip1) degradation. KPC thus probably controls degradation of p27(Kip1) in G1 phase after export of the latter from the nucleus.

Endoscopic bilateral drainage using SEMS for malignant hilar biliary obstruction is more effective than unilateral drainage in terms of cumulative stent patency, especially in cases of cholangiocarcinoma.

The IDUS findings were useful for distinction of IgG4-SC from cholangiocarcinoma. Transpapillary biopsy was not useful for direct diagnosis of IgG4-SC even after IgG4 immunostaining, but it did allow distinction of IgG4-SC from cholangiocarcinoma in some cases. IDUS and transpapillary biopsy after endoscopic retrograde cholangiopancreatography can provide further information for precise diagnosis of IgG4-SC.

The serine threonine kinase Akt is a core survival factor that underlies a variety of human diseases. Although regulatory phosphorylation and dephosphorylation have been well documented, the other posttranslational mechanisms that modulate Akt activity remain unclear. We show here that tetratricopeptide repeat domain 3 (TTC3) is an E3 ligase that interacts with Akt. TTC3 contains a canonical RING finger motif, a pair of tetratricopeptide motifs, a putative Akt phosphorylation site, and nuclear localization signals, and is encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. Moreover, DS cells exhibit elevated TTC3 expression, reduced phosphorylated Akt, and accumulation in the G(2)M phase, which can be reversed by TTC3 siRNA or Myr-Akt. Thus, interaction between TTC3 and Akt may contribute to the clinical symptoms of DS.

The expression of the ubiquitin-like molecule ISG15 and protein modification by ISG15 (ISGylation) are strongly activated by interferon, genotoxic stress, and pathogen infection, suggesting that ISG15 plays an important role in innate immune responses. 4EHP is an mRNA 5 cap structure-binding protein and acts as a translation suppressor by competing with eIF4E for binding to the cap structure. Here, we report that 4EHP is modified by ISG15 and ISGylated 4EHP has a much higher cap structure-binding activity. These data suggest that ISGylation of 4EHP may play an important role in cap structuredependent translation control in immune responses.Supplemental material is available at http://www.genesdev.org.Received July 19, 2006; revised version accepted December 19, 2006. ISG15 was the first reported ubiquitin-like modifier (ubl) (Haas et al. 1987). It forms covalent conjugates with cellular proteins similar to protein ubiquitylation (Loeb and Haas 1992). ISG15 expression and protein modification by ISG15 (ISGylation) are strongly activated by Type I interferon (IFN) (Farrell et al. 1979;Loeb and Haas 1992). IFNs are critical cytokines involved in innate immune responses (Garcia-Sastre and Biron 2006). These facts suggest that ISG15 modification may modulate certain immune responses related to pathogen infections and various stresses. Similar to protein ubiquitylation, ISGylation is also regulated by a set of enzymes. UBE1L is an ISG15 E1 enzyme, which shows high homology with the ubiquitin E1 (Yuan and Krug 2001). USP18 (UBP43) has been identified as a deISGylating isopeptidase (Malakhov et al. 2002). Recently, ubiquitin E2 enzymes UbcH6 and UbcH8 have been determined to function also as ISG15 conjugating enzymes (Kim et al. 2004;Zhao et al. 2004;. UbcH8 is reported to interact with several ubiquitin E3 ligases to mediate protein ubiquitylation . The fact that UbcH8 functions as a dual E2 enzyme for both ubiquitin and ISG15 raises the possibility that some UbcH8-interacting ubiquitin E3 ligases can function as an ISG15 E3 ligase. In fact, we have recently reported that the UbcH8 partner Efp ubiquitin ligase functions as an E3 for 14-3-3 ISGylation (Zou and Zhang 2006).The binding of eukaryotic translation initiation factor 4F (eIF4F) to the mRNA 5Ј cap structure is the rate-limiting step of cap structure-dependent translation initiation in eukaryotes (Gingras et al. 1999). eIF4F contains cap-binding protein eIF4E, scaffold protein eIF4G, and RNA helicase eIF4A. The interaction between eIF4E and eIF4G results in a conformational change of both proteins and enhances the association between eIF4E and the RNA cap structure (Gross et al. 2003). There are three eIF4E-family members in mammals termed eIF4E-1 (eIF4E), eIF4E-2 (4EHP and 4E-LP), and eIF4E-3 (Rom et al. 1998;Joshi et al. 2004). Like prototypical eIF4E, 4EHP is expressed ubiquitously; however, expression of eIF4E-3 is detected only in heart, skeletal muscle, lung, and spleen (Joshi et al. 2004). Similar to eIF4E, both 4EHP and eIF4E-3 bind to the RNA 5Ј cap...

The incidence of complications is higher for side-by-side than stent-in stent deployment in bilateral metal stenting. In terms of cumulative stent patency, side-by-side deployment tends to be more effective than stent-in-stent deployment.