Notch Signalling Mediated by Skip/Bx42 Dependent Gene and Cell Cycle Regulation


We previously characterized Bx42/SKIP a conserved chromatin co-regulator protein. As in Drosophila the mammalian homologue interacts with nuclear components of the Notch pathway like Notch-IC and Su(H)/CBF1. By induced Bx42-RNAi we demonstrated that these interactions are biologically important since the expression of several Notch target genes is dependent of the presence of Bx42/SKIP and tissue specific knock down of Bx42/SKIP results in Notch-like phenotypes. We currently map the interaction sites of Bx42/SKIP with Notch-IC, Su(H) and the Hairless protein. In contrast to suggested models we mapped the Skip interaction side on the C-term of Notch-IC downstream of the ankyrin repeats and the RAM domain. Work is in progress to investigate how the Skip/Notch-IC interaction is translated into the activation of target genes Expression of the most conserved part of Skip, the central SNW region, results in dominant negative phenotypes that are suppressed by over-expression of the Skip protein, by Notch gain of function mutations or putative Skip interacting proteins and enhanced by Notch loss of function alleles. Over-expression of SNW region in late larval eye discs results in a small eye phenotype by specific suppression of the Notch-dependent division of retinal precursor cells at the G2-M transition that is cyclin A dependent. Comparing the expression profile of the Bx42 dominant negative to wild type cells on microarrays we find that a restricted number of genes is affected by SNW over-expression, amongst them Dp, a dimerization partner of E2F and the chromatin repressor protein Sina. Interestingly, in mammalian cells Bx42/SKIP interacts with and counteracts the repressive effect of the Rb protein and shows an interaction with the E2F family of cell cycle regulators. The role of Skip and interacting proteins in cell cycle regulation will be investigated in more detail in Drosophila cell cultures.


Projektleitung
Saumweber, Harald Prof. i.R. Dr. rer. nat. (Details) (Zytogenetik)

Laufzeit
Projektstart: 02/2011
Projektende: 02/2014

Publikationen
Negeri, D., Eggert, H., Gienapp, R. and Saumweber, H. (2002) Inducible RNA interference uncovers the Drosophila protein Bx42 as an essential nuclear cofactor involved in Notch signal transduction. Mech. Dev. 117, 151-162.

Zuletzt aktualisiert 2020-25-11 um 15:50