VACM-1, a cul-5 gene, inhibits cellular growth by a mechanism that involves MAPK and p53 signaling pathways

Dort, C. Van; Zhao, Ping; Parmelee, K.; Capps, Byron E.; Poël, Amanda Van de; Listenberger, Laura L.; Kossoris, J.; Wasilevich, B.; Murrey, Douglas A.; Clare, Paula M.; Burnatowska-Hledin, Maria

doi:10.1152/ajpcell.00338.2002

Cited by 31 publications

(33 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Heterologous CUL5 expression has been reported to exert an antiproliferative effect (32,33). Furthermore, a clinical study showed a significant decrease in CUL5 expression in breast tumors versus matched normal tissue (34).…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells

Samant

Clarke

Workman

2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The molecular chaperone heat shock protein 90 (HSP90) is required for the activity and stability of its client proteins. Pharmacologic inhibition of HSP90 leads to the ubiquitin-mediated degradation of clients, particularly activated or mutant oncogenic protein kinases. Client ubiquitination occurs via the action of one or more E3 ubiquitin ligases. We sought to identify the role of Cullin-RING family E3 ubiquitin ligases in the cellular response to HSP90 inhibition. Through a focused siRNA screen of 28 Cullin-RING ligase family members, we found that CUL5 and RBX2 were required for degradation of several HSP90 clients upon treatment of human cancer cells with the clinical HSP90 inhibitor 17-AAG. Surprisingly, silencing Cullin-5 (CUL5) also delayed the earlier loss of HSP90 client protein activity at the same time as delaying cochaperone dissociation from inhibited HSP90-client complexes. Expression of a dominant-negative CUL5 showed that NEDD8 conjugation of CUL5 is required for client degradation but not for loss of client activity or recruitment of clients and HSP90 to CUL5. Silencing CUL5 reduced cellular sensitivity to three distinct HSP90 inhibitors, across four cancer types driven by different protein kinases. Our results reveal the importance of CUL5 in multiple aspects of the cellular response to HSP90 inhibition.eat shock protein 90 (HSP90) is a molecular chaperone that facilitates the stabilization and activation of around 350 client proteins (see www.picard.ch/downloads/Hsp90interactors. pdf for an updated client protein list) (1). As well as being involved in a wide range of normal cellular processes, many HSP90 clients are oncogenic kinases that are hyperactivated by mutation or amplified/overexpressed in malignancies (2, 3). HSP90-mediated activation and stabilization of client proteins requires an ATP-driven chaperone cycle regulated by a number of cochaperones (4, 5). Pharmacologic inhibition of HSP90 disrupts this cycle and leads to the ubiquitin-mediated proteasomal degradation of client proteins (3, 6, 7).The proposed model is that clients are ubiquitinated and thus targeted to the proteasome by the action of one or more E3 ubiquitin ligases (8). Some evidence suggests that the U boxcontaining ligase CHIP is involved in the degradation of certain HSP90 clients (9, 10). However, the stability of protein kinase clients such as ERBB2 is not increased in CHIP −/− cells treated with the first-in-class pharmacologic HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin [17-AAG, tanespimycin (11)] (10), suggesting that other E3 ubiquitin ligases are also involved.One study showed that the Cullin-RING ligase Cullin-5 (CUL5) is recruited to HSP90-containing complexes and is involved in the ubiquitination and degradation of the client ERBB2 following HSP90 inhibition (12). Cullin-RING ligases function as modular, multisubunit complexes that consist of a Cullin scaffold, a RING-H2 finger protein, a substrate-recognition subunit, and, in most cases, an adaptor that links the Cullin to the substrate reco...

show abstract

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells

Samant

Clarke

Workman

2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The purified ASB2 complex was incubated with various combinations of Uba1, Ubc5a, GST-Ubiquitin (GST-Ub) in the absence or presence of ATP to assess its ability to stimulate ubiquitination by Ubc5 by Western blot using anti-GST antibodies. more, expression of Cul5 protein inhibits cell growth and retards cytokinesis by a mechanism that involves p53 (43). Although the mechanism by which Cul5 functions in these processes remains unclear, Cul5-containing ECS ubiquitin ligases have been shown to regulate the turnover of molecules involved in cell-cycle control.…”

Section: Discussionmentioning

confidence: 99%

ASB2 Is an Elongin BC-interacting Protein That Can Assemble with Cullin 5 and Rbx1 to Reconstitute an E3 Ubiquitin Ligase Complex

Heuzé

Guibal

Banks

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The ankyrin repeat-containing protein with a suppressor of cytokine signaling box-2 (ASB2) gene was identified as a retinoic acid-response gene and a target of the promyelocytic leukemia-retinoic acid receptor-␣ oncogenic protein characteristic of acute promyelocytic leukemia. Expression of ASB2 in myeloid leukemia cells inhibits growth and promotes commitment, recapitulating an early step known to be critical for differentiation. Here we show that ASB2, by interacting with the Elongin BC complex, can assemble with Cullin5⅐Rbx1 to form an E3 ubiquitin ligase complex that stimulates polyubiquitination by the E2 ubiquitin-conjugating enzyme Ubc5. This is a first indication that a member of the ASB protein family, ASB2, is a subunit of an ECS (Elongin C-Cullin-SOCS box)-type E3 ubiquitin ligase complex. Altogether, our results strongly suggest that ASB2 targets specific proteins to destruction by the proteasome in leukemia cells that have been induced to differentiate.

show abstract

“…Three G-protein coupled receptors (V1a, V1b, and V2) mediate the biological influence of AVP [2,3]. Additionally, the vasopressin-activated calcium mobilizing (VACM) protein has been described as a putative AVP receptor, although very little is known about its role in cell function [4]. Generally, signaling through the V1 receptors can involve the activation of phospholipase A2, C, D, and protein kinase C, leading to an increase in intracellular free Ca 2+ , and the activation of the mitogen-activated protein kinase (MAPK) and focal adhesion kinase (FAK).…”

Section: Introductionmentioning

confidence: 99%

Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies

Keegan

Akerman

Péqueux

et al. 2005

Breast Cancer Res Treat

View full text Add to dashboard Cite

SummaryThe arginine vasopressin (AVP) gene is expressed in certain cancers such as breast cancer, where it is believed to act as an autocrine growth factor. However, little is known about the regulation of the AVP protein precursor (proAVP) or AVP-mediated signaling in breast cancer and this study was undertaken to address some of the basic issues. The cultured cell lines examined (Mcf7, Skbr3, BT474, ZR75, Mcf10a) and human breast cancer tissue extract were found to express proAVP mRNA. Western analysis revealed multiple forms of proAVP protein were present in cell lysates, corresponding to those detected in human hypothalamus extracts. Monoclonal antibodies directed against different regions of proAVP bound to intact live Mcf7 and Skbr3 cells. Dexamethasone increased the amount of proAVP-associated glycopeptide (VAG) secreted by Skbr3 cells and a combination of dexamethasone, IBMX and 8br-cAMP increased cellular levels of VAG. Exogenous AVP (1, 10, and 100 nM) elevated phospho-ERK1/2 levels, and increased cell proliferation was observed in the presence of 10 nM AVP. Concurrent treatment with the V1a receptor antagonist SR49059 reduced the effects of AVP on proliferation in Mcf7 cells, and abolished it in Skbr3 cells. Results here show that proAVP components are found at the surface of Skbr3 and Mcf7 cells and are also secreted from these cells. In addition, they show that AVP promotes cancer cell growth, apparently through a Vl-type receptor-mediated pathway and subsequent ERK1/2 activation. Thus, strategies for targeting proAVP should be examined for their effectiveness in diagnosing and treating breast cancer.Keywords : arginine vasopressin (AVP) ; pro-arginine vasopressin (proAVP) ; vasopressin-associated glycopeptide (VAG) ; monoclonal antibody (mAb) ; extracellular signal-regulated kinase (ERK) ; neurophysinrelated surface antigen (NRSA)

show abstract

VACM-1, a cul-5 gene, inhibits cellular growth by a mechanism that involves MAPK and p53 signaling pathways

Cited by 31 publications

References 31 publications

E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells

E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells

ASB2 Is an Elongin BC-interacting Protein That Can Assemble with Cullin 5 and Rbx1 to Reconstitute an E3 Ubiquitin Ligase Complex

Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies

Contact Info

Product

Resources

About