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Drosophila tumor suppressor Scribble has been identified as an apical-basolateral polarity determinant in epithelia. A human homolog of Drosophila Scribble, human Scribble (hScrib), has been identified as a protein targeted by human papillomavirus E6 for the ubiquitin-mediated degradation dependent on E6AP, a cellular ubiquitin-protein ligase. Human Scribble is classified as a LAP protein, having leucine-rich repeats (LRRs) and PDZ domains. We investigated whether hScrib, which is thought to have a role in polarity determination based on the data of its Drosophila homolog, is involved in cell-cycle regulation and proliferation control of epithelia. Transfection of hScrib inhibits cell-cycle progression from G1 to S phase, and it up- and down-regulates expression of adenomatous polyposis coli and cyclins A and D1, respectively. Knockdown of hScrib expression by siRNA leads to cell-cycle progression from G1 to S phase. We explored functional domain mapping to reveal which domains of hScrib are critical for its cellular proliferation control and localization at the basolateral membrane. We found that LRRs and PDZ domain 1 are indispensable for hScrib to inhibit cell growth by blocking cell-cycle progression and to keep its proper localization. These data indicate that basolateral membrane localization of hScrib is closely related to its proliferation control. Our findings suggest the possibility that hScrib is involved in signal transduction to negatively regulate cell proliferation by localizing at the basolateral membrane of epithelial cells through LRRs and PDZ domains. (Cancer Sci 2006; 97: 1217–1225)

Human scribble (hScrib), which was identified as substrate of human papillomavirus (HPV) E6 for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP, is a human homolog of Drosophila neoplastic tumor suppressor scribble, in which mutation causes loss of polarity and overgrowth of epithelia. Drosophila discs large (Dlg) is one of neoplastic tumor suppressors, which genetically links to scribble. E6 also targets human Dlg (hDlg) for ubiquitin-mediated degradation. Ubiquitin-protein ligase involved in this process has not been identified thus far. Here we investigated mechanism underlying degradation of three target proteins of E6, hScrib, hDlg, and p53 by using eighteen HPV 16 E6 mutants with single amino acid substitution. In vitro degradation ability of each E6 mutant was equivalent for these tumor suppressors. We investigated whether E6AP is involved in ubiquitin-mediated degradation of hDlg. In vitro binding assay revealed that hDlg formed ternary complex with E6–E6AP complex. The ability of E6 mutants to degrade these tumor suppressors was correlated with their ability to interact with E6AP. Furthermore, hDlg was targeted for in vitro ubiquitination in the presence of both E6 and E6AP. These data revealed that E6AP is extensively involved in the ubiquitin-mediated degradation of E6-dependent substrates as a cellular E3 ubiquitin-protein ligase. J. Med. Virol. 78:501–507, 2006. © 2006 Wiley-Liss, Inc.

リピオドール併用肝動脈塞栓術 (以下Lp-TAE) が非腫瘍部のエネルギー代謝に及ぼす影響を検討するために, Lp-TAEを施行した13症例を対象として, 肝硬変 (以下LC) の有無により2群に分け検討した. 一般肝機能は, LC (-), LC (+) 群ともにLp-TAE後4週以内に前値に回復した. ICGR15, ICGK値は, LC (-), LC (+) 群ともにLp-TAE後有意の変動を示さなかった. Lipid emulsion testからみたphagocytic indexは, LC (-), LC (+) 群ともにLp-TAE後高値を示すが, 2週目には前値に復しその後漸減して4週目でも低値を示す傾向にあった. 動脈血中ケトン体比は, LC (-) 群では, Lp-TAE後一過性の低下を示すが4週目には前値に復しているのに対し, LC (+) 群では4週目でも有意の低値を示し, 肝エネルギー代謝面での影響の残存が示唆された.

臨床肝血管腫3例と犬肝血管腫27病巣に肝血管造影,肝シンチグラムおよび血液生化学的検査を行い,その診断方法について検討した.血管造影で動脈相での栄養血管の拡張,血管性に富んだ異常血管群の出現,動脈相初期より静脈相にかけて明瞭にみられる斑状陰影により,臨床的に1.5×1.5cm大の血管腫を診断することが出来,小さな肝細胞癌との鑑別も可能であっだ.大きな血管腫では肝動脈枝の腫瘍による圧排,変位がみられ,腫瘍内に多数の新生血管やA-V shuntsが認められ,大きな肝細胞癌との鑑別が困難であった.犬肝血管腫では0.4×0.5cm大のものまで診断可能であり,直接3倍拡大撮影法を用いると0.4×0.3cm大の血管腫の質的診断まで可能となった.肝シンチグラムや血液生化学的検査は診断的価値はなかった.以上の事から肝血管造影が血管腫の診断に最も有用である結果が得られた.また肝血管腫の治療方針について自験例に文献的考察を加えて検討した.