Thursday, August 26, 2010


F-box and WD repeat domain containing-7 (Fbxw7) Targets Endoplasmic Reticulum-Anchored Osteogenic and Chondrogenic Transcriptional Factors for Degradation.

"We recently developed a new approach, termed DiPIUS (differential proteomics-based identification of ubiquitylation substrates), for the discovery of substrates of ubiquitin ligases. We have now applied DiPIUS to Fbxw7, the F-box protein component of an SCF-type ubiquitin ligase, and thereby identified two similar transcription factors, OASIS[also known as CREB3L1 which is upregulated by LSJL] and BBF2H7[aka CREB3L2], as candidate substrates. Co-immunoprecipitation analysis confirmed that the α and γ isoforms of Fbxw7 interact with OASIS and BBF2H7 in vivo. Sustained overexpression of Fbxw7 resulted in marked down-regulation of OASIS and BBF2H7, whereas RNAi-mediated Fbxw7 depletion stabilized both proteins. Mutation of a putative Cdc4 phosphodegron in OASIS and BBF2H7 attenuated their association with Fbxw7 and resulted in their stabilization. Depletion of Fbxw7 promoted the differentiation of mouse C2C12 mesenchymal cells into osteoblasts in association with the accumulation of OASIS. Conversely, overexpression of Fbxw7 in C2C12 cells resulted in down-regulation of Col1A1 mRNA, a target of OASIS. Conditional ablation of Fbxw7 in primary mouse mesenchymal cells promoted chondrogenesis in association with up-regulation of BBF2H7, whereas overexpression of Fbxw7 inhibited chondrogenesis in ATDC5 cells. Collectively, our results suggest that OASIS and BBF2H7 are bona fide substrates of Fbxw7, and that Fbxw7 controls osteogenesis and chondrogenesis by targeting OASIS and BBF2H7, respectively, for degradation."

Sometimes Fbxw7 is pro-chondrogenic and somtimes anti-.

"BBF2H7 is highly expressed in the proliferating zone of cartilage in developing long bones"

"Type II collagen (Col2) and cartilage oligomeric matrix protein (COMP) accumulate in the ER lumen of BBF2H7-deficient chondrocytes. BBF2H7 directly activates transcription of the gene for Sec23a, a component of coat protein complex II responsible for protein transport from the ER to the Golgi apparatus, suggesting that BBF2H7 controls the secretion of extracellular matrix molecules in cartilage by regulating vesicle transport."

"The full-length (FL) forms of OASIS and BBF2H7 are cleaved in response to ER stress, and the released NH2-terminal cytoplasmic domain (N) of each protein activates the transcription of target genes. Fbxw7 exists in three isoforms (Fbxw7α, Fbxw7β, and Fbxw7γ) that differ in their NH2-terminal regions and subcellular distributions. Fbxw7α is localized to the nucleus, Fbxw7β shows a cytoplasmic distribution suggestive of localization to the ER and Golgi apparatus, and
Fbxw7γ is predominantly nucleolar, suggesting that each isoform might interact with a different set of substrates."

"Notch suppresses the differentiation and proliferation of early chondrogenic cells, suggesting that the accumulation of Notch1 induced by depletion of Fbxw7 might inhibit chondrocyte differentiation."

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