SCF ubiquitin ligases in the maintenance of genome stability

Silverman, Joshua; Skaar, Jeffrey R.; Pagano, Michele

doi:10.1016/j.tibs.2011.10.004

Cited by 89 publications

(74 citation statements)

References 84 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, the SCF (Skp1-cullin-F-box) E3 complex directs phosphoproteins to be ubiquitinated and destroyed (14,15). In many cases, phosphorylationmediated protein destruction involves the peptidyl-prolyl cistrans isomerase Pin1, which binds phosphorylated S/T-P motifs and enhances a normally slow cis-trans isomerization of the peptide bond.…”

mentioning

confidence: 99%

An Unusual Two-Step Control of CPEB Destruction by Pin1

Nechama

Lin

Richter

2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

Cytoplasmic polyadenylation is a conserved mechanism that controls mRNA translation and stability. A key protein that promotes polyadenylation-induced translation of mRNAs in maturing Xenopus oocytes is the cytoplasmic polyadenylation element binding protein (CPEB). During this meiotic transition, CPEB is subjected to phosphorylation-dependent ubiquitination and partial destruction, which is necessary for successive waves of polyadenylation of distinct mRNAs. Here we identify the peptidylprolyl cis-trans isomerase Pin1 as an important factor mediating CPEB destruction. Pin1 interacts with CPEB in an unusual manner in which it occurs prior to CPEB phosphorylation and prior to Pin1 activation by serine 71 dephosphorylation. Upon induction of maturation, CPEB becomes phosphorylated, which occurs simultaneously with Pin1 dephosphorylation. At this time, the CPEB-Pin1 interaction requires cdk1-catalyzed CPEB phosphorylation on S/T-P motifs. Subsequent CPEB ubiquitination and destruction are mediated by a conformational change induced by Pin1 isomerization of CPEB. Similar to M phase progression in maturing Xenopus oocytes, the destruction of CPEB during the mammalian cell cycle requires Pin1 as well. These data identify Pin1 as a new and essential factor regulating CPEB degradation.

show abstract

mentioning

confidence: 99%

An Unusual Two-Step Control of CPEB Destruction by Pin1

Nechama

Lin

Richter

2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In this model, substitution of serine residues 303 and 307 to glutamic acid or alanine led to repression or derepression, respectively of the Hsf1 activation domain, suggesting that these phosphorylation sites exert intermolecular influence on Hsf1 protein (11). More recent evidence suggest that in addition to transcriptional repression of Hsf1 under normal physiological growth conditions, the phosphorylation of S303/S307 facilitates its binding to Fbxw7α ubiquitin ligase leading to its degradation through the SCF (Skp1-Cul1-Fbox) complex (17,18,35). Both Kourtis, et.…”

Section: Discussionmentioning

confidence: 91%

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

et al. 2017

View full text Add to dashboard Cite

“…Specifically, the functional status of FBXO4, the specificity factor of the SCF Fbxo4 E3 ligase that directs polyubiquitylation of the phosphorylated cyclin D1 (22, 23), has not been examined in melanoma. Fbxo4 belongs to a superfamily of F-box proteins, which function as substrate specificity factors for Skp1-Cul1-F-box (SCF) ubiquitin ligase complexes (24,25). Importantly, Fbxo4 deficiency leads to nuclear accumulation of cyclin D1, which in turn promotes cyclin D1-dependent cellular transformation (23,26,27).…”

mentioning

confidence: 99%

The FBXO4 Tumor Suppressor Functions as a Barrier to Braf^V600E-Dependent Metastatic Melanoma

Lee

Lian

D’Andrea

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

g Cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6) dysregulation is a major contributor to melanomagenesis. Clinical evidence has revealed that p16 INK4A , an allosteric inhibitor of CDK4/6, is inactivated in over half of human melanomas, and numerous animal models have demonstrated that p16 INK4A deletion promotes melanoma. FBXO4, a specificity factor for the E3 ligase that directs timely cyclin D1 proteolysis, has not been studied in melanoma. We demonstrate that Fbxo4 deficiency induces Brafdriven melanoma and that this phenotype depends on cyclin D1 accumulation in mice, underscoring the importance of this ubiquitin ligase in tumor suppression. Furthermore, we have identified a substrate-binding mutation, FBXO4 I377M, that selectively disrupts cyclin D1 degradation while preserving proteolysis of the other known FBXO4 substrate, TRF1. The I377M mutation and Fbxo4 deficiency result in nuclear accumulation of cyclin D1, a key transforming neoplastic event. Collectively, these data provide evidence that FBXO4 dysfunction, as a mechanism for cyclin D1 overexpression, is a contributor to human malignancy. Despite recent advances in immunotherapy and targeted therapy, metastatic melanoma remains an intractable, malignant disease with limited therapeutic options. The most widely appreciated genetic insult associated with melanoma is the constitutive activation of BRAF, a consequence of a valine-to-glutamate substitution at codon 600 (BRAF V600E ) (1-3). The importance of BRAF activation is underscored by its presence in roughly half of all cutaneous melanomas (4) and by the impressive cytotoxicity and tumor regression observed in melanoma patients receiving the BRAF kinase inhibitor vemurafenib (5-7).Attempts to model melanoma initially revealed that BRAF V600E expression in primary melanocytes elicits oncogene-induced senescence (8-10), as opposed to malignant growth. Consistently, ϳ80% of benign human nevi harbor BRAF V600E and never progress to melanoma (4). Thus, while BRAF-driven signaling may be an integral component of melanomagenesis, cooperation with other genetic insults is necessary.Multiple independent lines of evidence indicate that the loss of p16 INK4A , an allosteric inhibitor of cyclin-dependent kinase 4/6 (CDK4/6)-cyclin D, cooperates with RAS-RAF to induce melanoma (11-17). These oncogenic events are clinically significant, as p16INK4A is commonly inactivated in melanomas (18,19). In addition to p16 INK4A , the cyclin D1 gene (CCND1) is amplified in multiple melanoma subtypes (over 40% of acral melanomas) (20), also contributing to dysregulated CDK4/cyclin D1 activity.While amplification events contribute to increased cyclin D1 expression, roughly 20% of melanomas overexpressing cyclin D1 do not exhibit genetic alterations in CCND1 (20). The latter observation suggests that dysregulated posttranslational control may contribute to cyclin D1 overexpression. However, the role of the degradation machinery for cyclin D1, a highly labile protein (21), has not been extensively studied outside the contex...

show abstract

SCF ubiquitin ligases in the maintenance of genome stability

Cited by 89 publications

References 84 publications

An Unusual Two-Step Control of CPEB Destruction by Pin1

An Unusual Two-Step Control of CPEB Destruction by Pin1

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

The FBXO4 Tumor Suppressor Functions as a Barrier to Braf^V600E-Dependent Metastatic Melanoma

Contact Info

Product

Resources

About

SCF ubiquitin ligases in the maintenance of genome stability

Cited by 89 publications

References 84 publications

An Unusual Two-Step Control of CPEB Destruction by Pin1

An Unusual Two-Step Control of CPEB Destruction by Pin1

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

The FBXO4 Tumor Suppressor Functions as a Barrier to BrafV600E-Dependent Metastatic Melanoma

Contact Info

Product

Resources

About

The FBXO4 Tumor Suppressor Functions as a Barrier to Braf^V600E-Dependent Metastatic Melanoma