Set them free: F-box protein exchange by Cand1

Flick, Karin; Kaiser, Peter

doi:10.1038/cr.2013.55

Cited by 11 publications

(17 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CAND1 binds to unneddylated CUL1 and regulates the formation of the SCF ubiquitin E3 ligase complex, thus regulating ubiquitindependent proteolysis of many regulatory proteins [15,21,22]. It is also known that CAND1 modulates SCF complexes [16,[23][24][25]. The present data suggest that CAND1 deubiquitylates rabphilin-3A.…”

Section: Discussionsupporting

confidence: 55%

“…CAND1 regulates the formation of the SCF (SKP1, CUL1, F-box proteins) ubiquitin ligase complex, and its binding to the complex results in reduced substrate ubiquitylation [15,16]. Overexpression experiments using plasmid constructs were performed in PC12 cells to investigate the effects of CAND1 on rabphilin-3A ubiquitylation.…”

Section: Cand1 Deubiquitylates Rabphilin-3a In Pc12 Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Cullin-associated NEDD8-dissociated protein 1, a novel interactor of rabphilin-3A, deubiquitylates rabphilin-3A and regulates arginine vasopressin secretion in PC12 cells

et al. 2018

View full text Add to dashboard Cite

Abstract. The molecular mechanism involved in the exocytosis of arginine vasopressin (AVP) is not fully known. Rabphilin-3A has been suggested as a novel autoantigen in infundibulo-neurohypophysitis (LINH), which leads to central diabetes insipidus through insufficient secretion of AVP. However, the role of rabphilin-3A in the pathogenesis of LINH remains unclear. Thus, the aim of the present study was to identify proteins binding rabphilin-3A in the posterior pituitary. Using glutathione S-transferase (GST)-pulldown assays and proteomic analyses, cullin-associated NEDD8-dissociated protein 1 (CAND1) was identified as a rabphilin-3A-binding protein in the posterior pituitary. Co-immunoprecipitation assays indicated that CAND1 interacted endogenously with rabphilin-3A. In addition, immunohistochemistry experiments showed that CAND1 immunoreactivity was detected mainly in the posterior pituitary, intermediate lobe, and the supraoptic nucleus in the hypothalamus, and less in the anterior lobe, partially co-localizing with rabphilin-3A. Overexpression of CAND1 resulted in deubiquitylation of rabphilin-3A in PC12 cells. Moreover, overexpression of CAND1 in PC12 cells co-transfected with AVP enhanced both basal and KCl-stimulated AVP secretion. The findings indicate that CAND1 inhibits the ubiquitylation of rabphilin-3A and positively regulates AVP secretion. These data shed light on a novel potential mechanism involving rabphilin-3A in AVP secretion, and suggest a new role of CAND1 as a regulator of hormone or neurotransmitter secretion.Key words: Vasopressin, Rabphilin-3A, Cullin-associated NEDD8-dissociated protein 1, Deubiquitylation, Secretion doi:10.1507/endocrj.EJ17-0399 ARGININE VASOPRESSIN (AVP) is a hormone secreted from the posterior pituitary through exocytosis, a process involving numerous steps [1][2][3]. Rabphilin-3A has been suggested as a major autoantigen in infundibuloneurohypophysitis (LINH) and autoantibodies against rabphilin-3A may be useful as diagnostic markers for LINH [4]. Rabphilin-3A is a specific GTP-Rab3A-binding protein on secretory granules [5,6], regulating neurotransmitter release, and acting in conjunction with synaptosomal-associated protein 25 (SNAP25), Rab27A, and syntaxin 1 [7][8][9][10][11]. Although the involvement of Submitted Sep. 11, 2017; Accepted Nov. 30, 2017 as EJ17-0399 Released online in J-STAGE as advance publication Jan. 23, 2018Correspondence to: Yoshihisa Sugimura, Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University, 1-98 Dengakugakubo, Toyoake, Aichi 470-1192, Japan. E-mail: sugiyosi@med.nagoya-u.ac.jp rabphilin-3A in AVP secretion has not been previously characterized, preliminary data showed that rabphilin-3A may be involved in the docking and fusion of AVP vesicles, thereby regulating AVP release and water homeostasis in the body. However, the detailed mechanism of AVP release mediated by rabphilin-3A in the posterior pituitary is largely unknown.The aim of this study was to identify new interactors of rabphili...

show abstract

Section: Discussionsupporting

confidence: 55%

Section: Cand1 Deubiquitylates Rabphilin-3a In Pc12 Cellsmentioning

confidence: 99%

Cullin-associated NEDD8-dissociated protein 1, a novel interactor of rabphilin-3A, deubiquitylates rabphilin-3A and regulates arginine vasopressin secretion in PC12 cells

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Other required functions included the COP9 signalosome (CSN) and a PPI sub-network defined by CAND1/NEDD8 (Figure 3E). CSN and CAND1/NEDD8 regulate SKP1/CUL1/F-box (SCF) complexes (Flick and Kaiser, 2013). While the core SKP1/CUL1 complex showed no subtype specificity, several F-box genes were selectively essential in basal A lines, including FBXW11/β-TrCP2 (Table S3B).…”

Section: Resultsmentioning

confidence: 99%

Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance

Marcotte

Sayad

Brown

et al. 2016

Cell

418

531

View full text Add to dashboard Cite

Summary Large-scale genomic studies have identified multiple somatic aberrations in breast cancer, including copy number alterations, and point mutations. Still, identifying causal variants and emergent vulnerabilities that arise as a consequence of genetic alterations remain major challenges. We performed whole genome shRNA “dropout screens” on 77 breast cancer cell lines. Using a hierarchical linear regression algorithm to score our screen results and integrate them with accompanying detailed genetic and proteomic information, we identify vulnerabilities in breast cancer, including candidate “drivers,” and reveal general functional genomic properties of cancer cells. Comparisons of gene essentiality with drug sensitivity data suggest potential resistance mechanisms, effects of existing anti-cancer drugs, and opportunities for combination therapy. Finally, we demonstrate the utility of this large dataset by identifying BRD4 as a potential target in luminal breast cancer, and PIK3CA mutations as a resistance determinant for BET-inhibitors.

show abstract

“…CAND1 stimulates ubiquitylation of some substrates by facilitating the exchange of Cullins with different CRL adaptor-substrate modules [ 36 ]. Hypothetical modulators of CAND1 are predicted to have cell-type and context-dependent effects on different CRLs and their ubiquitin substrates [ 25 ]. Our data indicates that C60 perturbs CAND1 interaction with Cullin 1.…”

Section: Discussionmentioning

confidence: 99%

“…BPLF1 was shown to block the interaction of Cullin with the Cullin-associated and neddylation-dissociated 1 (CAND1) protein. CAND1 is an F-box exchange factor required for loading substrates onto the CRL complex required for ubiquitylation and proteasome degradation of numerous protein substrates [ 25 ]. CAND1 is thought to regulate the exchange of the Cullin-ROC1 module with different SKP1-F-box substrate complexes [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation

et al. 2017

View full text Add to dashboard Cite

The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53.

show abstract

Set them free: F-box protein exchange by Cand1

Cited by 11 publications

References 11 publications

Cullin-associated NEDD8-dissociated protein 1, a novel interactor of rabphilin-3A, deubiquitylates rabphilin-3A and regulates arginine vasopressin secretion in PC12 cells

Cullin-associated NEDD8-dissociated protein 1, a novel interactor of rabphilin-3A, deubiquitylates rabphilin-3A and regulates arginine vasopressin secretion in PC12 cells

Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance

Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation

Contact Info

Product

Resources

About