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The role of SCF Skp2 and SCF β‐TrCP1/2 in the cerebellar granule cell precursors
Author(s) -
Yamashita Mariko,
Owa Tomoo,
Shiraishi Ryo,
Adachi Toma,
Ichijo Kentaro,
Taya Shinichiro,
Miyashita Satoshi,
Hoshino Mikio
Publication year - 2020
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12813
Subject(s) - biology , ubiquitin ligase , skp1 , f box protein , gene knockdown , microbiology and biotechnology , cell growth , ubiquitin , cell culture , biochemistry , gene , genetics
A proper balance between proliferation and differentiation of cerebellar granule cell precursors (GCPs) is required for appropriate cerebellar morphogenesis. The Skp1‐Cullin1‐F‐box (SCF) complex, an E3 ubiquitin ligase complex, is involved in polyubiquitination and subsequent degradation of various cell cycle regulators and transcription factors. However, it remains unknown how the SCF complex affects proliferation and differentiation of GCPs. In this study, we found that the scaffold protein Cullin1, and F‐box proteins Skp2, β‐TrCP1 and β‐TrCP2 are expressed in the external granule layer (EGL). Knockdown of these molecules in the EGL showed that Cullin1, Skp2 and β‐TrCP2 enhanced differentiation of GCPs. We also observed accumulation of cyclin‐dependent kinase inhibitor p27 in GCPs when treated with a Cullin1 inhibitor or proteasome inhibitor. Furthermore, knockdown of p27 rescued enhancement of differentiation by Cullin1 knockdown. These results suggest that the SCF complex is involved in the maintenance of the proliferative state of GCPs through p27 degradation. In addition, inhibition of Cullin1 activity also prevented cell proliferation and enhanced accumulation of p27 in Daoy cells, a cell line derived from the sonic hedgehog subtype of medulloblastoma. This suggested that excess degradation of p27 through the SCF complex causes overproliferation of medulloblastoma cells.