Oncogene database

6790

AURKA

aurora kinase A;AURKA;aurora kinase A

ARK-1|Aurora-A kinase|IPL1-related kinase|aurora 2|aurora-related kinase 1|aurora/IPL1-like kinase|aurora/IPL1-related kinase 1|breast tumor-amplified kinase|breast-tumor-amplified kinase|hARK1|protein phosphatase 1, regulatory subunit 47|serine/threonine

20q13

protein-coding

PURPOSE: Multiple chromosome abnormalities, including gain of chromosome20q, have been detected frequently in human pancreatic cancers. Overexpression of the STK15/BTAK/Aurora A gene located on chromosome 20q13, which encodes a centrosome-associated serine/threonine kinase, has been shown to induce chromosomal instability, leading to aneuploidy and cell transformation in multiple in vitro experimental systems. The purpose of this study was to investigate the expression and copy number alteration of STK15 in pancreatic cancer. EXPERIMENTAL DESIGN: STK15 expression at both the mRNA and protein levels together with the copy number of STK15 gene was measured in nine pancreatic carcinoma cell lines: (a) HPAF-II; (b) Aspc-1; (c) Panc-1; (d) Panc-3; (e) Panc-28; (f) Panc-48; (g) HS766T; (h) MIAPaCa-2; and (i) BxPc3. STK15 protein expression was also examined in normal pancreatic tissues and tumors by Western blotting and immunohistochemistry. RESULTS: STK15 was overexpressed in ALL of the nine cell lines examined, but gene amplification was infrequent. Western Blot analysis of primary tumor tissues revealed 2-10 times overexpression of STK15 protein compared with normal adjacent tissues from pancreatic cancer patients. Concurrent overexpression of cdc20, an STK15-associated protein, and reduced expression of cdc25, a mitosis-activating protein phosphatase, were detected in the same tumor samples. Elevated STK15 protein expression was detected in 22 of 38 tumor sections (58%) from pancreatic cancer patients. The extent of STK15 expression was not significantly correlated with the size, degree of differentiation, and metastasis status of the tumors. CONCLUSIONS: These results show that STK15 is overexpressed in pancreatic tumors and carcinoma cell lines and suggest that overexpression of STK15 may play a role in pancreatic carcinogenesis.

PURPOSE: Aurora-A/STK15/BTAK, a centrosome-associated oncogenic protein, is implicated in the control of mitosis. Overexpression of Aurora-A has been shown to result in chromosomal aberration and genomic instability. Multiple lines of evidence indicate that Aurora-A induces cell malignant transformation. In the current study, we are interested in investigating the expression of Aurora-A in human esophageal squamous cell carcinoma (ESCC) and characterizing the association of Aurora-A with ESCCmalignant progression. EXPERIMENTAL DESIGN: Aurora-A protein expression was examined in 84 ESCC tissues and 81 paired normal adjacent tissues by either immunohistochemistry or Western blot analysis. In addition, a gene-knockdown small interfering RNA technique was used in ESCC cells to investigate whether Aurora-A contributes to the ability of a tumor to grow invasively. RESULTS: The amount of Aurora-A protein in ESCC was considerably higher than that in normal adjacent tissues. Overexpression of Aurora-A was observed in 57 of 84 (67.5%) ESCC samples. In contrast, <2% of normal adjacent tissue displayed high expression of Aurora-A. Interestingly, overexpression of Aurora-A seemed to correlate with the invasive malignancy of ESCC. Disruption of endogenous Aurora-A using small interfering RNA technique substantially suppressed cell migrating ability. CONCLUSION: The findings presented in this report show that Aurora-A expression is elevated in human esophageal squamous cell carcinoma and is possibly associated with tumor invasion, indicating that overexpression of Aurora-A may contribute to ESCC occurrence and progression.

Proper chromosome segregation is required to maintain the appropriate number of chromosomes from one cell generation to another and to prevent aneuploidy, which is mainly found in solid cancers. A correct mitotic spindle is necessary to accomplish such a process. Aurora kinases play critical roles in chromosome segregation and cell division; their deregulation impairs spindle assembly, checkpoint function and cell division causing chromosome mis-segregation. These kinases have been implicated in tumorigenesis. Aurora-A (AurA), in particular has been identified as a cancer-susceptibility gene, is overexpressed in a number of tumors and is required for G2/M transition and spindle assembly. ASAP is a novel spindle-associated protein, the deregulation of which induces severe mitotic defects. We show here that ASAP is a novel substrate of AurA kinase. We have identified serine 625 as the major phosphorylation site for AurA in vivo and localized the phosphorylated form of ASAP to centrosomes from late G2 to telophase, and around the midbody during cytokinesis. AurA depletion induces a proteasome-dependent degradation of ASAP. ASAP depletion induces spindle defects rescued by the expression of the phosphorylation-mimetic mutant ASAP-S625E and not by the non-phosphorylatable mutant ASAP-S625A. Microinjection of mono-specific S625 phospho-antibodies also impaired spindle formation and mitosis. These results strongly indicate that the phosphorylation of ASAP on S625 by AurA is required for bipolar spindle assembly and is essential for a correct mitotic progression. ALL together, these results suggest that we have identified a novel AurA substrate, pointing out ASAP as a new potential target for antitumoral drugs.

The Aurora-A kinase regulates cell division by phosphorylating multiple downstream targets in the mitotic apparatus. Aurora-A is frequently overexpressed in tumor cells and it is therefore regarded as a novel candidate target in anti-cancer therapy. Its actual contribution to cell transformation, however, is not entirely clarified; furthermore, its transforming ability has been found to vary broadly depending on the systems and experimental conditions in which it was assayed. This variability suggests that Aurora-A overexpression requires the concomitant deregulation of partner factor(s) to fully elicit its oncogenic potential. Molecular and structural studies indicate that the full activation and correct mitotic localisation of Aurora-A require its interaction with the spindle regulator TPX2. In this review we propose a brief reappraisal of Aurora-A intrinsic oncogenic features. We then present literature screening data indicating that TPX2 is also overexpressed in many tumor types, and, furthermore, that Aurora-A and TPX2 are frequently co-overexpressed. We therefore propose that the association of Aurora-A and TPX2 gives rise to a novel functional unit with oncogenic properties. We also suggest that some of the roles that are conventionally attributed to Aurora-A in cell transformation and tumorigenesis could in fact be a consequence of the oncogenic activation of this unit.

BACKGROUND: ZNF217 is a candidate oncogene located at 20q13, a chromosomal region frequently amplified in breast cancers. The precise mechanisms involved in ZNF217 pro-survival function are currently unknown, and utmost importance is given to deciphering the role of ZNF217 in cancer therapy response. RESULTS: We provide evidence that stable overexpression of ZNF217 in MDA-MB-231 breast cancer cells conferred resistance to paclitaxel, stimulated cell proliferation in vitro associated with aberrant expression of several cyclins, and increased tumor growth in mouse xenograft models. Conversely, siRNA-mediated silencing of ZNF217 expression in MCF7 breast cancer cells, which possess high endogenous levels of ZNF217, led to decreased cell proliferation and increased sensitivity to paclitaxel. The paclitaxel resistance developed by ZNF217-overexpressing MDA-MB-231 cells was not mediated by the ABCB1/PgP transporter. However, ZNF217 was able to counteract the apoptotic signals mediated by paclitaxel as a consequence of alterations in the intrinsic apoptotic pathway through constitutive deregulation of the balance of Bcl-2 family proteins. Interestingly, ZNF217 expression levels were correlated with the oncogenic kinase Aurora-A expression levels, as ZNF217 overexpression led to increased expression of the Aurora-A protein, whereas ZNF217 silencing was associated with low Aurora-A expression levels. We showed that a potent Aurora-A kinase inhibitor was able to reverse paclitaxel resistance in the ZNF217-overexpressing cells. CONCLUSION: Altogether, these data suggest that ZNF217 might play an important role in breast neoplastic progression and chemoresistance, and that Aurora-A might be involved in ZNF217-mediated effects.

BACKGROUND: Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. RESULTS: As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA s primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. CONCLUSIONS: PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms influencing CIN and its consequences on tumour growth are largely unknown. We identified an increase in microtubule plus-end assembly rates as a mechanism influencing CIN in colorectal cancer cells. This phenotype is induced by overexpression of the oncogene AURKA or by loss of the tumour suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and influencing CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumour growth in vitro and in vivo. Thus, we identify a fundamental mechanism influencing CIN in cancer cells and reveal its adverse consequence on tumour growth.