Mechanisms of Tumor Suppression by the SCFFbw7

“…Importantly, FBXW7 is a tumor suppressor. [13][14][15] It is found mutated in numerous cancers 13,[16][17][18] and is mapped to 4q32, which is a site of heterozygosity loss in a number of cancers. 19 Furthermore, it is one of the p53-dependent genes involved in tumorigenesis.…”

Section: Fbxw7 Is Involved In Aurora B Degradationmentioning

confidence: 99%

FBXW7 is involved in Aurora B degradation

et al. 2012

View full text Add to dashboard Cite

“…In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15)(16)(17)(18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19)(20)(21). c-MYC ubiquitination is antagonized by the deubiquitinase USP28, which "piggybacks" on FBW7 and stabilizes c-MYC protein (22).…”

Section: Introductionmentioning

confidence: 99%

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

128

141

View full text Add to dashboard Cite

R e s e a R c h a R t i c l e3 4 0 7 jci.org Volume 124 Number 8 August 2014 IntroductionThe intestine is made up of repetitive units that consist of a differentiated compartment (the villus) and a proliferative compartment (the crypt). Intestinal stem cells are located in the crypt (1, 2) and produce rapidly proliferating daughter cells, the transit amplifying cells, which subsequently differentiate into 2 main epithelial lineages. The absorptive lineage is composed of all enterocytes, while the secretory lineage is composed of goblet cells (secreting protective mucins), enteroendocrine cells (secreting hormones like serotonin or secretin), and Paneth cells (3, 4). Whether transit amplifying cells differentiate along an absorptive or a secretory lineage is regulated by the Notch pathway (5). Engagement of Notch receptors by Notch ligands, such as Delta or Jagged, induces proteolytic cleavage of the receptor by γ-secretase. The cleaved NOTCH1 receptor (NICD1) translocates into the nucleus, resulting in the formation of an active transcriptional complex composed of RBPJκ (also known as CSL or CBF1) and NICD1. Notch signal activation induces hairy/enhancer of split (Hes) gene expression. Ablation of Notch signaling via genetic deletion of Rbpj results in secretory cell expansion (6). Conversely, in transgenic mice overexpressing NICD1, goblet cells are absent, and the proliferative compartment is expanded (7).The Wnt signaling pathway is a key regulator of intestinal stem cell homeostasis (8), and 2 of the target genes induced by Wnt signaling, c-MYC and c-JUN, encode transcription factors that have oncogenic potential (9, 10). Consequently, aberrant activation of the adenomatous polyposis coli/β-catenin/T cell factor (APC/ β-catenin/TCF) pathway is an initiating event in the majority of human colorectal cancers (11).c-MYC is a transcription factor with key functions in cell differentiation and cancer development (12)(13)(14). In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15-18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19-21). c-MYC ubiquitination is antagonized by the deubiquitinase USP28, which "piggybacks" on FBW7 and stabilizes c-MYC protein (22). Thus, an E3 ubiquitin ligase and a deubiquitinase, FBW7 and USP28, are together recruited to substrates (22), and a cycle of deubiquitination and ubiquitination controls c-MYC stability.Genomic data from human cancers suggest that most colorectal cancer mutations converge on c-MYC misregulation (23). Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24-29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting ...

show abstract

“…Binding-Fbw7 is a member of the F-box family of ubiquitin ligases that target substrate proteins for ubiquitination as part of specific SCF complexes (29,30). We used in vitro ubiquitination assays to test whether Fbw7 could ubiquitinate SREBP1 in response to DNA binding.…”

Section: Fbw7-dependent Ubiquitination Of Srebp1 In Response To Dnamentioning

confidence: 99%

Phosphorylation and Ubiquitination of the Transcription Factor Sterol Regulatory Element-binding Protein-1 in Response to DNA Binding

Punga¹,

Bengoechea-Alonso²,

Ericsson

2006

Journal of Biological Chemistry

109

View full text Add to dashboard Cite

Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors control cholesterol and lipid metabolism and play critical roles during adipocyte differentiation. The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr 426 and Ser 430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3␤-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding. DNA binding enhances the direct interaction between the C-terminal domain of SREBP1 and GSK-3␤. Accordingly, we demonstrate that GSK-3␤ is recruited to the promoters of SREBP target genes in vivo. As a result of the phosphorylation of Thr 426 and Ser 430 , the ubiquitin ligase Fbw7 is recruited to SREBP molecules associated with target promoters. Using a reconstituted ubiquitination system, we demonstrate that Fbw7-mediated ubiquitination of SREBP1 is dependent on its DNA binding activity. Thus, DNA binding could provide a mechanistic link between the phosphorylation, ubiquitination, and degradation of active transcription factors.Members of the sterol regulatory element-binding protein (SREBP) 3 family of transcription factors control cholesterol and lipid metabolism and play critical roles during adipocyte differentiation and insulin signaling (1, 2). The SREBP family of transcription factors consists of three different SREBP proteins; SREBP1a, SREBP1c, and SREBP2. The SREBPs are synthesized as large precursor proteins that are inserted into the nuclear and endoplasmic reticulum membranes and are transcriptionally inactive (3). In sterol-depleted cells, SREBPs are processed sequentially by two membrane-associated proteases that release the mature form of the proteins (4, 5). These transcriptionally active fragments of the SREBPs are translocated to the nucleus and bind to the promoters of SREBP target genes (6). It has been demonstrated that the mature forms of SREBPs are modified by phosphorylation (7-9), acetylation (10), sumoylation (11), and ubiquitination (8, 12), and it has been shown that these modifications regulate their stability and/or transcriptional activity.Many transcription factors, particularly those involved in the control of cell growth, are unstable proteins targeted for degradation by the ubiquitin-proteasome system (13). Numerous observations have pointed to the existence of a close connection between the ubiquitin-proteasome system and transcriptional activation (14,15). It has been demonstrated that the sequences that specify proteolysis of some activators overlap with their transcriptional activation domains and that components of the proteasome can be recruited to promoters through interactions with transcriptional regulators (16 -21). It has also been demonstrated that the activity of certain transcription factors can be enhanced by ubiquitination or through interactions with specific ubiquitin ligases (22-25). However, the mechanistic link between the transcriptional activity of...

show abstract

Mechanisms of Tumor Suppression by the SCFFbw7

Cited by 106 publications

References 56 publications

FBXW7 is involved in Aurora B degradation

FBXW7 is involved in Aurora B degradation

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Phosphorylation and Ubiquitination of the Transcription Factor Sterol Regulatory Element-binding Protein-1 in Response to DNA Binding

Contact Info

Product

Resources

About