The N-terminal domain of the Aurora-A Phe-31 variant encodes an E3 ubiquitin ligase and mediates ubiquitination of IκBα

Briassouli, Paraskevi; Chan, Florence; Linardopoulos, Spiros

doi:10.1093/hmg/ddl410

Cited by 9 publications

(8 citation statements)

References 30 publications

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“…In fact, multiple cancer associated mutations in Aurora-A have been identified, of which, some alter the kinase activity and others create or abolish protein interaction (110–112). As mentioned earlier, I31F polymorphism in Aurora-A can activate NF-κB pathway through preferential UBE2N interaction to down-regulate I B (28,113). Another V57I polymorphism in Aurora-A shows reduced kinase activity and correlates with aneuploidy.…”

Section: The Future Of Cancer Therapeutics With Aurora Kinase Inhimentioning

confidence: 83%

Aurora kinase inhibitors as anticancer molecules

Katayama

Sen

2010

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

126

101

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Aurora kinase family of serine/threonine kinases are important regulators of mitosis that are frequently over expressed in human cancers and have been implicated in oncogenic transformation including development of chromosomal instability in cancer cells. In humans, among the three members of the kinase family, Aurora-A, -B and -C, only Aurora-A and -B are expressed in detectable levels in somatic cells undergoing mitotic cell division and have been characterized in greater detail for their involvement in cellular pathways relevant to the development of cancer associated phenotypes. Aurora-A and -B are being investigated as potential targets for anticancer therapy. Development of inhibitors against Aurora kinases as anticancer molecules gained attention because of the facts that aberrant expression of these kinases lead to chromosomal instability and derangement of multiple tumor suppressor and oncoprotein regulated pathways. Pre-clinical studies and early phase I and II clinical trials of multiple Aurora kinase inhibitors as targeted anticancer drugs have provided encouraging results. This article discusses functional involvement of Aurora kinase-A and -B in the regulation of cancer relevant cellular phenotypes together with findings on some of the better characterized Aurora kinase inhibitors in modulating the functional interactions of Aurora kinases. Future possibilities about developing next generation Aurora kinase inhibitors and their clinical utility as anticancer therapeutic drugs are also discussed.

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Section: The Future Of Cancer Therapeutics With Aurora Kinase Inhimentioning

confidence: 83%

Aurora kinase inhibitors as anticancer molecules

Katayama

Sen

2010

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

126

101

View full text Add to dashboard Cite

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“…To confirm the specificity of AKCI for AURKC, we performed in vitro kinase assays using recombinant AURKA, which is known to interact with IκBα [ 21 ]. As shown in Figure 6G , activation of IκBα by AURKA was not altered by AKCI treatment.…”

Section: Resultsmentioning

confidence: 99%

A small-molecule inhibitor targeting the AURKC-IκBα interaction decreases transformed growth of MDA-MB-231 breast cancer cells

et al. 2017

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The Aurora kinases, Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) or meiosis (AURKC). Several Aurora kinase inhibitors are being investigated as novel anticancer therapeutics. Recent studies demonstrated that AURKC activation contributes to breast cancer cell transformation. Therefore, AURKC is both a promising marker and therapeutic target for breast cancer; however, its signaling network has not been fully characterized. Using translocation-based cellular assays, we identified IκBα as a binding partner of AURKC, and found that AURKC phosphorylates IκBα at Ser32, thereby activating it. In silico modeling and computational analyses revealed a small-molecule inhibitor (AKCI) that blocked the AURKC–IκBα interaction and exerted antitumor activity in MDA-MB-231 breast cancer cells. Specifically, AKCI induced G2/M cell-cycle arrest through modulation of the p53/p21/CDC2/cyclin B1 pathways. In addition, the drug significantly inhibited MDA-MB-231 cell migration and invasion, as well as decreasing colony formation and tumor growth. Via its interaction with IκBα, AURKC indirectly induced NF-κB activation; accordingly, AKCI decreased PMA-induced activation of NF-κB. Thus, the small-molecule inhibitor AKCI represents a first step towards developing targeted inhibitors of AURKC protein binding, which may lead to further advances in the treatment of breast cancer.

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“…A polymorphism in Aurora‐A gene, Phe31Ile has been identified and Aurora‐A Phe31 but not Ile31 has been shown to interact with UBE2N, E2 ubiquitin ligase [Ewart‐Toland et al, 2003]. It has been demonstrated that Aurora‐A Phe 31 not Ile31, in a complex with UBE2N transiently over expressed, has an intrinsic E3 ubiquitin ligase activity and catalyses polyubiquitination of both Aurora‐A itself for protein stabilization and IκBα for protein degradation [Briassouli et al, 2006]. It appears that the previous study utilized Aurora‐A Phe31 isoform, while our study utilized the Ile31 isoform expression construct.…”

Section: Discussionmentioning

confidence: 99%

Aurora‐A kinase phosphorylation of Aurora‐A kinase interacting protein (AIP) and stabilization of the enzyme‐substrate complex

Katayama

Sasai

Czerniak

et al. 2007

J of Cellular Biochemistry

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Aurora-A is an oncogenic kinase that plays essential roles in mitosis as well as cell survival. Aurora-A interacting protein (AIP) was identified as a negative regulator of Aurora-A with its ectopic over expression inducing destabilization of Aurora-A protein. Here we present evidence that in human cells, contrary to the earlier report, AIP functions in stabilizing rather than destabilizing Aurora-A. Furthermore, AIP is phosphorylated on Serine 70 by Aurora-A but not Aurora-B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. We observed that when co-expressed with AIP, protein levels of both Aurora-A and Aurora-B are markedly elevated regardless of their kinase activities and phosphorylation state of AIP. Interaction of Aurora kinases with AIP is necessary for this elevated stability. This phenomenon is commonly detected in several human cancer cell lines used in this study. Depletion of AIP by RNA interference decreased Aurora-A but not Aurora-B in two of the three cell lines analyzed, indicating that under physiological condition, AIP functions in stabilization of Aurora-A but not Aurora-B, though this regulation may be dependent on additional factors as well. Further, AIP siRNA induced cell cycle arrest at G2/M, which is consistent with anticipated loss of function of Aurora-A in these cells. Thus, our study provides the first evidence of a role for AIP in G2/M cell cycle progression by cooperatively regulating protein stabilization of its up-stream regulator, Aurora-A kinase through protein-protein interaction as well as protein phosphorylation.

show abstract

The N-terminal domain of the Aurora-A Phe-31 variant encodes an E3 ubiquitin ligase and mediates ubiquitination of IκBα

Cited by 9 publications

References 30 publications

Aurora kinase inhibitors as anticancer molecules

Aurora kinase inhibitors as anticancer molecules

A small-molecule inhibitor targeting the AURKC-IκBα interaction decreases transformed growth of MDA-MB-231 breast cancer cells

Aurora‐A kinase phosphorylation of Aurora‐A kinase interacting protein (AIP) and stabilization of the enzyme‐substrate complex

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