Supplementary Figure 1: Phylogenetic Tree of Selected Apc2/Cullin Protein Family Members

Supplementary Figure 1: Phylogenetic tree of selected Apc2/cullin protein family members NCBI-PSI-Blast searches with Saccharomyces cerevisiae Apc2 identified a single mouse orthologue (XP_130088.1) and no paralogues.

List of NCBI-nr gi numbers: At5g46210.1_At (18422645), At4g02570.1_At (18411983), At1g02980.1_At (22329305), T10P11.14.1_At (7484879), At1g69670.1_At (15222412), At1g26830.1_At (15223361), At2g04660.1_At (15224042), K06H7.6_Ce (17554086), CUL-5_Ce (17559070), CUL-3_Ce (2493902), CUL-4_Ce (17532635), CUL-2_Ce (25815091), CUL-6_Ce (17539492), Cul-1_Ce (17552768), CG8711-PA_Dm (24586500), CG1401-PA_Dm (24650935), CG1512-PB_Dm (19921636), CG11861-PA_Dm (17737421), CG1877-PD_Dm (17647593), CG3060-PA_Dm (20130331), CUL-1_Hs (19863257), CUL-3_Hs (4503165), CUL-4A_Hs (11140811), CUL-2_Hs (1923243), KIAA0708_Hs (24307991), gi2394274_Hs (2394274), APC2_Hs (7019327), KIAA0076_Hs (7661894), CUL-4B_Hs (23958537), CUL-3_Mm (7710014), gi26328507_Mm (26328507), gi26327761_Mm (26327761), CUL1_Mm (7549752), gi20073115_Mm (20073115), Apc2_Mm (26329467), YGR003w_Sc (6321440), Apc2_Sc (6323156), Rtt101_Sc (6322414), Cdc53_Sc (6320070), Pcu1_Sp (11359308), Pcu4_Sp (19115107), Apc2_Sp (19112608), SPAC24H6.03_Sp (2130361).

Supplementary Figure 2: Levels of ALT, GLDH and bilirubin are increased in affected Apc2Δ/floxMx-Cre mice In affected Apc2Δ/floxMx-Cre mice ALT, GLDH and bilirubin levels were elevated, whereas in unaffected Apc2Δ/floxMx-Cre as well as in Apc2Δ/floxMx-Cre livers ALT, GLDH and bilirubin were within normal range. 5 affected Apc2Δ/floxMx-Cre, 5 unaffected Apc2Δ/floxMx-Cre and 5 Apc2Δ/floxmice were used to calculate mean value and standard deviation. Wirth et al. 2

Supplementary Figure 3: Quantification of TUNEL positive cells (A) In Apc2Δ/floxMx-Cre as well as in Apc2Δ/flox mice at day 0, 1, 2, 3, 4 and 5 after pI/C-injection the number of apoptotic cells was below 1 %. (n=3 for each time point). (B) In affected Apc2Δ/floxMx-Cre mice shortly before death 6 % of apoptotic cells were detected, whereas the number of TUNEL positive cells in unaffected Apc2Δ/floxMx-Cre livers as well as in Apc2Δ/flox livers was below 1 % (n=3).

Supplementary Figure 4. Quantification of Ki67 positive cells in Apc2flox/+Mx- Cre and Apc2Δ/flox livers at day 3, 7 and 28 after pI/C-injection pI/C was injected into Apc2flox/+Mx-Cre and Apc2Δ/flox mice and the number of Ki67 positive cells was determined at day 3, 7 and 28 after the first pI/C-injection. For day 7 and day 28 pI/C was injected twice within an interval of 72 hours. Compared to Apc2/flox which were not injected with pI/C we observed a minor increase of Ki67 positive cells below 3 % in pI/C-injected Apc2flox/+Mx-Cre as well as in the Apc2Δ/flox mice. 50-70 % Ki67 positive cells were measured in Apc2/floxMx–Cre livers at day 10-14 after pI/C-injection in affected livers.