New Insights into the Mechanism for VACM-1/cul5 Expression in Vascular Tissue in vivo

Burnatowska-Hledin, Maria; Barney, Christopher C.

doi:10.1016/b978-0-12-800177-6.00003-7

Cited by 4 publications

(4 citation statements)

References 103 publications

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“…The cullin-RING ligase (CRL) ubiquitin family, first reported in the late 1990s ( 1 ), has taken a central position in regulatory biology. One of seven members of the human cullin gene family, the ubiquitin ligase scaffold protein cullin-5 (CUL5) has been shown to be an important element in cardiovascular biology ( 17 ) and has been implicated in several types of cancers including breast cancer ( 2 , 3 ). We examined CUL5 expression in two histologic forms of endometrial (uterine) cancers; the less aggressive and better prognosis endometrioid adenocarcinoma and the more aggressive, poorer prognosis serous adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

et al. 2016

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Abstract. Altered expression of cullin-5 (CUL5), a member of the cullin-RING E3 ubiquitin ligase family, has been implicated in a number of types of cancers including breast, cervical and hepatocellular cancers. In the present study, we found that CUL5 expression was significantly decreased in both endometrioid and serous endometrial adenocarcinomas with the more aggressive serous type displaying a higher reduction (-4.3-fold) than the less aggressive endometrioid type (-2.9-fold). Overexpression of CUL5 mRNA and protein in Ishikawa H endometrial cancer cells resulted in decreased cell proliferation and in a reduction in CUL5-RING E3 ligase downstream clients JAK2 and FAS-L. Finally, we demonstrated for the first time that CUL5 is a direct target of miR-182 that we previously showed to be significantly overexpressed in endometrial adenocarcinomas and we provided evidence that increased miR-182 expression is, at least in part, a result of demethylation of its upstream promoter. These data suggest a cascade in which miR-182 expression is epigenetically increased leading to decreased CUL5 expression and increased cellular proliferation. The final step in the cascade may be operating through a decrease in ubiquitination of pro-growth CUL5 ubiquitin ligase clients. This cascade offers a series of potential interventional steps involving epigenetic modification, miRNA and/or gene targeting and ubiquitination.

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Section: Discussionmentioning

confidence: 99%

Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

et al. 2016

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“…VACM-1 is recognized as Cul5 because of its homology to the Caenorhabditis elegans gene Cul5 [ 2 , 3 ]. Cul5 is expressed in many cells and organs, including endothelial cells, brain, kidney collecting tubule cells, and vascular endothelial cells [ 2 , 4 – 6 , 7 ]. Cul5 inhibits cyclic AMP production, and this effect is reversed by staurosporin, a protein kinase A (PKA) inhibitor, or by mutating S730A, the PKA-dependent phosphorylation site in the Cul5 sequence in COS-1 cells [ 8 ].…”

Section: Identification and Regulation Of Cullinmentioning

confidence: 99%

The role of cullin 5-containing ubiquitin ligases

et al. 2016

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The suppressor of cytokine signaling (SOCS) box consists of the BC box and the cullin 5 (Cul5) box, which interact with Elongin BC and Cul5, respectively. SOCS box-containing proteins have ubiquitin ligase activity mediated by the formation of a complex with the scaffold protein Cul5 and the RING domain protein Rbx2, and are thereby members of the cullin RING ligase superfamily. Cul5-type ubiquitin ligases have a variety of substrates that are targeted for polyubiquitination and proteasomal degradation. Here, we review the current knowledge on the identification of Cul5 and the regulation of its expression, as well as the signaling pathways regulated by Cul5 and how viruses highjack the Cul5 system to overcome antiviral responses. Identification and regulation of cullin 5Cullin 5 (Cul5) was originally identified as a vasopressin-activated calcium-mobilizing (VACM-1) protein, an arginine vasopressin (AVP) receptor [1]. AVP is a nonapeptide that regulates body fluid and blood pressure homeostasis. VACM-1 is recognized as Cul5 because of its homology to the Caenorhabditis elegans gene Cul5 [2,3]. Cul5 is expressed in many cells and organs, including endothelial cells, brain, kidney collecting tubule cells, and vascular endothelial cells [2,[4][5][6]7]. Cul5 inhibits cyclic AMP production, and this effect is reversed by staurosporin, a protein kinase A (PKA) inhibitor, or by mutating S730A, the PKA-dependent phosphorylation site in the Cul5 sequence in COS-1 cells [8]. The inhibitory effect of Cul5 on AVP-stimulated cAMP production is enhanced by a protein kinase C inhibitor [8]. CUL-5 expression is downregulated in 82 % (41/50) of breast tumors compared with matched normal tissues [9]. Overexpression of Cul5 in T47D breast cancer cells decreases cell growth and mitogen activated protein kinase (MAPK) phosphorylation [10], and Cul5 overexpression downregulates early growth response 1 (EGR-1) protein expression and upregulates Fas-L mRNA expression [10]. The regulation of both MAPK and EGR-1 pathways by 17β-estradiol led to the examination of estrogen-dependent T47D cell growth, which showed that Cul5 inhibits basal and 17β-estradiol-dependent cell growth and MAPK phosphorylation [11].Resveratrol (trans-3,5,4′-trihydroxystilbene), which inhibits tumor initiation and promotion, is a natural component of the human diet, and its wide range of biological activities has been demonstrated in vivo and in vitro [12][13][14][15]. The antiproliferative effect of resveratrol is significantly enhanced by Cul5 overexpression in T47D cells [16].The expression of Cul5 is regulated by several stimuli and pathways (Fig. 1). Resveratrol upregulates Cul5 expression and decreases T47D cell growth, suggesting that the antiproliferative effect of resveratrol is mediated by Cul5 [16]. Cul5 is a flexible scaffold protein with a preferred distribution of conformational states [17], and NEDD8 modification (neddylation) alters the conformation of Cul5 and activates it [18]. Cul5(S730A) accelerates cellular proliferation and induces an...

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“… 24 In addition, Cul 5 has been identified to play positive roles in regulating cell growth, proliferation and physiological and other processes in the human body 25 and is expressed in many cells and organs, including endothelial cells, brain, kidney collecting tubule cells, and vascular endothelial cells. 11 , 26 While the importance of CRL5-dependent protein ubiquitination in cancers has been well-documented, 27 what role each CRL5 plays in the cardiovascular system has just started to come to light, our study demonstrated for the first time that Cul 5 participates in the pathogenesis of HPH. Cul 5 has been confirmed to regulate EC growth and may modulate angiogenesis.…”

Section: Discussionmentioning

confidence: 65%

“…It has been reported that Cul 5 is expressed in cultured rat endothelial cells, 10 which is an important element in cardiovascular biology. 11 At present, the role of Cul 5 in vascular diseases, especially PH, is under clarification. In a previous study, we have proved that HIF-1α/VEGF promotes HPH progression, 9 and it was reported that Cul-5 and TRAF6 interaction could lead to NF-κB activation, 12 which is an important direct modulator of HIF-1α expression.…”

Section: Introductionmentioning

confidence: 99%

Cullin 5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF

Wang,

Huang,

Zhang

et al. 2023

iScience

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New Insights into the Mechanism for VACM-1/cul5 Expression in Vascular Tissue in vivo

Cited by 4 publications

References 103 publications

Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182

The role of cullin 5-containing ubiquitin ligases

Cullin 5 aggravates hypoxic pulmonary hypertension by activating TRAF6/NF-κB/HIF-1α/VEGF

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