Aurora-A Kinase Interacting Protein (AIP), a Novel Negative Regulator of Human Aurora-A Kinase

Abstract

Aurora kinases have evolved as a new family of mitotic centrosome- and microtubule-associated kinases that regulate the structure and function of centrosomes and spindle. One of its members, Aurora-A, is a potential oncogene. Overexpression of Aurora-A is also implicated in defective centrosome duplication and segregation, leading to aneuploidy and tumorigenesis in various cancer cell types. However, the regulatory pathways for mammalian Aurora-A are not well understood. Exploiting the lethal phenotype associated with the overexpression of Aurora-A in yeast, we performed a dosage suppressor screen in yeast and report here the identification of a novel negative regulator of Aurora-A, named AIP (Aurora-A kinase Interacting Protein). AIP is a ubiquitously expressed nuclear protein that interacts specifically with human Aurora-A in vivo. Ectopic expression of AIP with Aurora-A in NIH 3T3 and COS cells results in the down-regulation of ectopically expressed Aurora-A protein levels, and this down-regulation is demonstrated to be the result of destabilization of Aurora-A through a proteasome-dependent protein degradation pathway. A noninteracting deletion mutant of AIP does not down-regulate Aurora-A protein, suggesting that the interaction is important for the protein degradation. AIP could therefore be a potential useful target gene for anti-tumor drugs. Aurora kinases have evolved as a new family of mitotic centrosome- and microtubule-associated kinases that regulate the structure and function of centrosomes and spindle. One of its members, Aurora-A, is a potential oncogene. Overexpression of Aurora-A is also implicated in defective centrosome duplication and segregation, leading to aneuploidy and tumorigenesis in various cancer cell types. However, the regulatory pathways for mammalian Aurora-A are not well understood. Exploiting the lethal phenotype associated with the overexpression of Aurora-A in yeast, we performed a dosage suppressor screen in yeast and report here the identification of a novel negative regulator of Aurora-A, named AIP (Aurora-A kinase Interacting Protein). AIP is a ubiquitously expressed nuclear protein that interacts specifically with human Aurora-A in vivo. Ectopic expression of AIP with Aurora-A in NIH 3T3 and COS cells results in the down-regulation of ectopically expressed Aurora-A protein levels, and this down-regulation is demonstrated to be the result of destabilization of Aurora-A through a proteasome-dependent protein degradation pathway. A noninteracting deletion mutant of AIP does not down-regulate Aurora-A protein, suggesting that the interaction is important for the protein degradation. AIP could therefore be a potential useful target gene for anti-tumor drugs. Faithful chromosome segregation and cytokinesis are two essential steps in mitosis, which is responsible for the viability and genetic stability of daughter cells. This involves the concerted spatial and temporal interactions among various components such as the chromosomes, centrosomes, actin, and the microtubule cytoskeleton. Defined at the molecular level, the stability and the activation/inactivation of the proteins associated with these structures result in the regulation of the chromosome, centrosome, spindle microtubules, and actin dynamics. Reversible protein phosphorylation plays an important regulatory role in orchestrating the interactions among various proteins during mitosis (1Verde F. Labbe J.C. Doree M. Karsenti E. Nature. 1990; 343: 233-238Google Scholar, 2Vandre D.D. Davis F.M. Rao P.N. Borisy G.G. Eur. J. Cell Biol. 1986; 41: 72-81Google Scholar, 3Vandre D.D. Davis F.M. Rao P.N. Borisy G.G. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 4439-4443Google Scholar, 4Nigg E.A. Blangy A. Lane H. Exp. Cell Res. 1996; 229: 174-180Google Scholar, 5Centonze V.E. Borisy G.G. J. Cell Sci. 1990; 95: 405-411Google Scholar, 6Vandre D.D. Borisy G.G. J. Cell Sci. 1989; 94: 245-258Google Scholar). Many of the protein kinases and their opposing phosphatases, which are involved in these signaling cascades, have been identified (7Nigg E.A. Ernst Schering Res. Found. Workshop. 2001; 34: 19-46Google Scholar). For example, the cyclin-dependent kinases are activated by cdc25 phosphatase (8Hoffmann I. Clarke P.R. Marcote M.J. Karsenti E. Draetta G. EMBO J. 1993; 12: 53-63Google Scholar) to regulate different stages of M phase, starting from triggering the mitotic entry, spindle formation, anaphase to cytokinesis (9Nigg E.A. Mol. Cell. Biol. 2001; 2: 21-31Google Scholar, 10Morgan D.O. Nature. 1995; 274: 131-134Google Scholar, 11Nigg E.A. BioEssays. 1995; 17: 471-480Google Scholar, 12Andersen S.S. BioEssays. 1999; 21: 53-60Google Scholar). Similarly, polo-like kinases regulate several processes, which include centrosome maturation, cyclin-dependent kinase 1 activation and inactivation, and cytokinesis (9Nigg E.A. Mol. Cell. Biol. 2001; 2: 21-31Google Scholar, 13Donaldson M.M. Tavares A.A. Hagan I.M. Nigg E.A. Glover D.M. J. Cell Sci. 2001; 114: 2357-2358Google Scholar, 14Nigg E.A. Curr. Opin. Cell Biol. 1998; 10: 776-783Google Scholar, 15Glover D.M. Hagan I.M. Tavares A.A. Genes Dev. 1998; 12: 3777-3787Google Scholar). Other participating kinases include Bub1 kinase, which localizes to the kinetochore and regulates the anaphase checkpoint (16Straight A.F. Curr. Biol. 1997; 7: R613-R616Google Scholar), and the centrosome-associated NimA-related kinase, which primarily regulates the centrosome cycles (17Mayor T. Meraldi P. Stierhof Y.D. Nigg E.A. Fry A.M. FEBS Lett. 1999; 45: 292-295Google Scholar). The stability of the mitotic regulators also plays a pivotal role in the progression and completion of mitosis. In mitotic cells, progression into anaphase depends on the activation of the anaphase-promoting complex/cyclosome (APC/C) 1The abbreviations used are: APC/C, anaphase-promoting complex/cyclosome; ALLM, N-acetyl-Leu-Leu-methional; ALLN, N-acetyl-Leu-Leu-norleucinal; EST, expressed sequence tag; HsAurora-A, human Aurora-A; MmAurora-B, mouse Aurora-B; SD, synthetic dropout; TBS, Tris-buffered saline; TR, N-terminal truncated.1The abbreviations used are: APC/C, anaphase-promoting complex/cyclosome; ALLM, N-acetyl-Leu-Leu-methional; ALLN, N-acetyl-Leu-Leu-norleucinal; EST, expressed sequence tag; HsAurora-A, human Aurora-A; MmAurora-B, mouse Aurora-B; SD, synthetic dropout; TBS, Tris-buffered saline; TR, N-terminal truncated. by phosphorylation to degrade the mitotic regulators (18Morgan D.O. Nat. Cell Biol. 1999; 1: E47-E53Google Scholar, 19Kotani S. Tanaka H. Yasuda H. Todokoro K. J. Cell Biol. 1999; 146: 791-800Google Scholar). Recently, the Aurora kinase family emerged as a new family of mitotic serine threonine kinases regulating the centrosomal and microtubule function, ensuring the accurate chromosome segregation and efficient completion of cytokinesis (20Giet R. Prigent C. J. Cell Sci. 1999; 112: 3591-3601Google Scholar, 21Bischoff J.R. Plowman G.D. Trends Cell Biol. 1999; 9: 454-459Google Scholar). The Aurora kinase family was first identified in the budding yeast as Ipl1 (22Chan C.S. Botstein D. Genetics. 1993; 135: 677-691Google Scholar), and subsequently various homologs of Ipl1 have been isolated from diverse organisms, ranging from Drosophila, Xenopus, Caenorhabditis elegans, mouse, rat, to human (20Giet R. Prigent C. J. Cell Sci. 1999; 112: 3591-3601Google Scholar, 21Bischoff J.R. Plowman G.D. Trends Cell Biol. 1999; 9: 454-459Google Scholar). Ipl1 is the only representative of this family in yeast, two Aurora-related kinases are found in Drosophila and C. elegans, and three in mammals (20Giet R. Prigent C. J. Cell Sci. 1999; 112: 3591-3601Google Scholar, 21Bischoff J.R. Plowman G.D. Trends Cell Biol. 1999; 9: 454-459Google Scholar). Their roles in chromosome segregation are implicated in the phenotypes of various mutants. S. cerevisiae ipl1 mutants showed abnormal chromosome segregation and ploidy (22Chan C.S. Botstein D. Genetics. 1993; 135: 677-691Google Scholar, 23Tung H.Y. Wang W. Chan C.S. Mol. Cell. Biol. 1995; 15: 6064-6074Google Scholar, 24Biggins S. Severin F.F. Bhalla N. Sassoon I. Hyman A.A. Murray A.W. Genes Dev. 1999; 13: 532-544Google Scholar). Drosophila Aurora mutants showed defective centrosome separation resulting in the formation of monopolar spindles (25Glover D.M. Leibowitz M.H. McLean D.A. Parry H. Cell. 1995; 81: 95-105Google Scholar). They share similarity in their kinase catalytic domain but no or little similarity in their N-terminal domain, which seems to be species- and member-specific. Their expression and kinase activity are tightly cell cycle-regulated, peaking at M phase and disappearing rapidly upon mitotic exit (26Niwa H. Abe K. Kunisada T. Yamamura K. Gene (Amst.). 1996; 169: 197-201Google Scholar, 27Kimura M. Kotani S. Hattori T. Sumi N. Yoshioka T. Todokoro K. Okano Y. J. Biol. Chem. 1997; 272: 13766-13771Google Scholar, 28Gopalan G. Chan C.S.M. Donovan P.J. J. Cell Biol. 1997; 138: 643-656Google Scholar, 29Bischoff J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar, 30Shindo M. Nakano H. Kuroyanagi H. Shirasawa T. Mihara M. Gilbert D.J. Jenkins N.A. Copeland N.G. Yagita H. Okumura K. Biochem. Biophys. Res. Commun. 1998; 244: 285-292Google Scholar). In mammals, there are three members of this family, designated Aurora-A, Aurora-B, and Aurora-C. Orthologs of Aurora-A kinase localize to the centrosome and mitotic spindle and function during the early part of the mitosis from prophase (27Kimura M. Kotani S. Hattori T. Sumi N. Yoshioka T. Todokoro K. Okano Y. J. Biol. Chem. 1997; 272: 13766-13771Google Scholar, 29Bischoff J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar,31Zhou H. Kuang J. Zhong L. Kuo W.L. Gray J.W. Sahin A. Brinkley B.R. Sen S. Nat. Genet. 1998; 20: 189-193Google Scholar, 49Tatsuka M. Katayama H. Ota T. Tanaka T. Odashima S. Suzuki F. Terada Y. Cancer Res. 1998; 58: 4811-4816Google Scholar). Aurora-B kinase localizes to the and during the mitosis, and plays a role in cytokinesis M. Nakano H. Kuroyanagi H. Shirasawa T. Mihara M. Gilbert D.J. Jenkins N.A. Copeland N.G. Yagita H. Okumura K. Biochem. Biophys. Res. Commun. 1998; 244: 285-292Google Scholar, Y. M. Suzuki F. Yasuda Y. S. M. EMBO J. 1998; 17: Scholar). kinase localizes to the anaphase centrosomes M. Y. Yoshioka T. Okano Y. J. Biol. Chem. 1999; 274: Scholar), and its function to be been on Aurora-A kinase of its role in Overexpression of Aurora-A kinase is in of and of J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar, H. Kuang J. Zhong L. Kuo W.L. Gray J.W. Sahin A. Brinkley B.R. Sen S. Nat. Genet. 1998; 20: 189-193Google Scholar). Aurora-A kinase to chromosome M. Nakano H. Kuroyanagi H. Shirasawa T. Mihara M. Gilbert D.J. Jenkins N.A. Copeland N.G. Yagita H. Okumura K. Biochem. Biophys. Res. Commun. 1998; 244: 285-292Google Scholar), which is in several human J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar, M.M. M. A. C. T. R. D. F. M. Kuo W.L. Cancer Res. Scholar, A. J. M. T. L. D. Gray J.W. F.M. Proc. Natl. Acad. Sci. U. S. A. Scholar, A. T. J. 1999; Scholar, F. M. C. G. P. D. M.M. R. C. J. 1996; Scholar, C. A. R. Y. M. K. K. Y. J. Abe T. H. J. 2001; Scholar). Ectopic overexpression of Aurora-A in cells centrosome and aneuploidy H. Kuang J. Zhong L. Kuo W.L. Gray J.W. Sahin A. Brinkley B.R. Sen S. Nat. Genet. 1998; 20: 189-193Google Scholar). overexpression of Aurora-A in cells suggesting that Aurora-A could function as a potential J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar, H. Kuang J. Zhong L. Kuo W.L. Gray J.W. Sahin A. Brinkley B.R. Sen S. Nat. Genet. 1998; 20: 189-193Google Scholar). The on the yeast into the role of Aurora-A kinase in mitosis. proteins J.R. G. L. Mol. Biol. Cell. 1997; Scholar), Tavares A.A. A. Glover D.M. Genes Dev. 1998; 12: Scholar) and R. R. F. K. Prigent C. J. Biol. Chem. 1999; 274: Scholar) found to with the Aurora kinase homologs in yeast and yeast Ipl1 is also found to with the kinetochore protein the role of Aurora kinase in the of the mitotic checkpoint the of the chromosome by the spindle microtubule S. Severin F.F. Bhalla N. Sassoon I. Hyman A.A. Murray A.W. Genes Dev. 1999; 13: 532-544Google Scholar, L. Wang W. Chan C.S. Mol. Cell. Biol. Scholar, I. Severin F.F. M.J. Hyman A.A. Genes Dev. 1999; 13: Scholar). Aurora-A kinase is to with F.M. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar), which is involved in the mitotic activation of anaphase-promoting G. H. Mol. Cell. 1998; 2: Scholar). only is on the of Aurora-A kinase in the of Aurora-A kinase and of the Aurora-A kinase signaling to have a of the role of the kinase in chromosome segregation and in an to proteins as well as the negative regulators of Aurora-A kinase, a dosage suppressor screen in which cell that in yeast been In this we report the identification of such potential negative regulator of Aurora-A was in the and protein as T. M. S. S. N. E. L. Wang J.C. Proc. Natl. Acad. Sci. U. S. A. Scholar). For cells to phase in and with of Aurora-A in and cell in the Curr. Genet. 1989; Scholar). The resulting on synthetic and which the by and synthetic and the which only on the by a AIP a was and for of AIP from the cell Aurora-A and AIP in the mammalian expression The expression was a from the a was at the of and AIP by as G. Chan C.S.M. Donovan P.J. J. Cell Biol. 1997; 138: 643-656Google Scholar). isolated from human and a human cancer cell from and used for with to and Gilbert Gilbert W. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: Scholar) with a AIP a and with to NIH 3T3 and COS cells in and cells in with of cell have been to the cells in a to the and with different at a of For the in interaction of or with different of or the of and of for Similarly, NIH 3T3 cells or COS cells in a to the For Aurora-A degradation cells with and AIP at different the of to The For cells on the in the 1 to the A of 1 of and of of used for protein COS cells with and for The cells for on in TBS, The by at for at The protein of the was by the to the 1 of was by with of of protein for 1 at For to the protein of F.M. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar) or of mouse was with of of protein for 1 at For the and protein and for at with TBS, and with TBS, The by with and by The proteins subsequently to with in TBS, the with or mouse at a of or mouse at at The also in and with the for 1 at The by and to AIP deletion mutants by deletion A and a from the and of of the The to the to the of mutant The different of AIP into for expression The of the deletion mutants by In interaction and degradation with these AIP mutants as on in for at for in TBS, cells with the mouse for 1 at The cells in and with the was used as the For cells with by a with a Overexpression of Aurora-A kinase is lethal in yeast J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar). the lethal phenotype of Aurora-A kinase, we to mammalian proteins that the lethal phenotype and the yeast from For this a was in yeast expression expression of the Aurora-A kinase in yeast is the was with this Aurora-A and a cell in expressed a and the resulting for of cell and by sequence of a of that a which we as the of the was The of these was by the from cell The of the and the from the by AIP to this The of the isolated by the suppressor screen in yeast is in 1 of the protein and sequence of AIP with the in the that is to the sequence to an protein with the a sequence to the as a part of the human sequence to human AIP found in mouse and 1 the sequence of AIP with the in the AIP and at the its with mouse and However, not found in the such as yeast, Drosophila, on the we that AIP is a novel gene and the AIP by of The AIP a that a with a molecular of of human and cancer cell that AIP is ubiquitously expressed in a of in and for the in AIP protein found a nuclear suggesting AIP could be a nuclear ectopically expressed AIP was to the nuclear of the cell expression and nuclear of AIP in human and cancer cell was with from The with the AIP from the yeast dosage suppressor The was and with cells with a AIP and the of the AIP protein was by with by of was with the to the nuclear of the AIP The dosage suppressor screen here to AIP is of the and of Aurora-A that AIP with Aurora-A kinase from the yeast in interaction the AIP with Aurora-A to in yeast not a interaction AIP and Aurora-A in mammalian cell we the AIP into cells and to the Aurora-A with the AIP The results in that AIP with Aurora-A in and that AIP be with Aurora-A, and Aurora-A be with AIP However, is that the interaction of AIP with the Aurora-A in was to that the in the could be by the of Aurora-A in cells. The result in a is the that is the the interaction cells that are in of Aurora-A protein not with with and by The results in that the AIP protein and Aurora-A protein be of or AIP been isolated as the negative regulator of Aurora-A kinase, we that interaction of AIP with Aurora-A kinase result in the down-regulation of the stability activity of Aurora-A In an to the of interaction on the Aurora-A protein, the of Aurora-A protein in cells to the of AIP overexpression on the of Aurora-A protein of which was not to the of AIP overexpression on Aurora-A NIH 3T3 or COS cells with AIP and expression at different and the of protein by A human was used to the human Aurora-A in the of the mouse and Aurora-A Ectopic expression of Aurora-A protein in human or cell in protein to be by with two different not In COS cells, expression of Aurora-A results in two of which the with the Aurora-A protein from cells not The of these at is not However, the results that could down-regulate the Aurora-A in a and AIP as well as the N-terminal of AIP to down-regulate Aurora-A protein not the AIP was efficient in that could the expressed Aurora-A protein in COS cells a and the of the interaction AIP and Aurora-A is a for the down-regulation of Aurora-A, we to a deletion mutant of AIP protein, which does not with Aurora-A A of deletion mutants from the or of AIP protein and used for Aurora-A interaction as The and of these in the different deletion mutants in to the AIP protein are in of these deletion mutants in as well as COS cells showed that these mutant proteins have stability not the mutant which showed This mutant the nuclear and to be the of nuclear is responsible for the stability and function of this However, of the deletion mutants be expressed in and COS cells. for the stability of the a of to Aurora-A was used of the in the interaction the of Aurora-A these the expression of protein was with that of mutant AIP the that the of protein in the are responsible for the of protein in the interaction the was from 1 as well as of protein The in that the mutants and with Aurora-A protein the protein However, the deletion mutant not interaction with Aurora-A protein of the of the mutant protein This that of AIP that are for the interaction with Aurora-A the of the noninteracting mutant in Aurora-A protein, an in degradation as was performed with the AIP as well as the AIP mutants. The results in that the noninteracting mutant was efficient in Aurora-A protein with the and deletion mutants. This that the interaction is important for the degradation of Aurora-A the of the of AIP overexpression on the down-regulation of Aurora-A protein, the of AIP overexpression on MmAurora-B, of the Aurora kinase family, as well as was The for is Aurora-A protein, the proteasome-dependent K. Mihara H. Y. A. Tanaka H. Yasuda H. K. T. Scholar, M. Murray A.W. Nature. Scholar) also COS cells with with or human at of and the of overexpression on the of these proteins The in a and that the overexpression of does not the down-regulation of or human and the that AIP Aurora-A protein the to down-regulate that the of AIP is not by the activation of the been the plays a role in the regulation of Aurora-A stability K. Mihara H. Y. A. Tanaka H. Yasuda H. K. T. Scholar). is that the of AIP overexpression on the down-regulation of Aurora-A could be through the of proteasome-dependent degradation of this COS cells with with or expression and the of AIP overexpression on the down-regulation of Aurora-A was in the and of such as ALLN, and in could the down-regulation of Aurora-A protein to different on their to the could not the degradation of Aurora-A protein, suggesting that the is to a role in the down-regulation of these results that the plays a role in down-regulation of Aurora-A Aurora-A kinase is a of a kinase family implicated in segregation of daughter cells. Aurora-A kinase is to a role also in tumorigenesis J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar). Overexpression of Aurora-A kinase cells and aneuploidy in cells H. Kuang J. Zhong L. Kuo W.L. Gray J.W. Sahin A. Brinkley B.R. Sen S. Nat. Genet. 1998; 20: 189-193Google Scholar). of Aurora-A kinase expression and activity at such as gene and degradation through the proteasome-dependent J.R. Anderson L. Zhu Y. Mossie K. Ng L. Souza B. Schryver B. Flanagan P. Clairvoyant F. Ginther C. Chan C.S. Novotny M. Slamon D.J. Plowman G.D. EMBO J. 1998; 17: 3052-3065Google Scholar, H. Kuang J. Zhong L. Kuo W.L. Gray J.W. Sahin A. Brinkley B.R. Sen S. Nat. Genet. 1998; 20: 189-193Google Scholar, K. Mihara H. Y. A. Tanaka H. Yasuda H. K. T. Scholar). are to the of Aurora-A kinase at the molecular In this a dosage suppressor screen in yeast, we have isolated and a novel negative regulator of Aurora-A have that AIP interacts specifically and Aurora-A kinase by its degradation through the proteasome-dependent pathway. demonstrated that the and N-terminal AIP could with Aurora-A kinase, suggesting that the of AIP is for the However, the interaction of Aurora-A kinase with AIP in cells AIP was to of the degradation of protein by This was by the that Aurora-A protein by the of Aurora-A and AIP and Aurora-A kinase be a and Similarly, and AIP in the down-regulation of Aurora-A kinase not However, the AIP was efficient in the down-regulation of the of the protein the cell or the to Aurora-A The of AIP was from of that the cells of the AIP the AIP of the mutant AIP proteins for the of Aurora-A protein demonstrated that the mutant the essential for the and the interaction is important for the degradation of Aurora-A kinase this mutant the nuclear suggesting that the of AIP to the be for the interaction and degradation of Aurora-A have that AIP Aurora-A kinase through proteasome-dependent degradation. AIP is not in that there are of proteins involved in the degradation of cell through the pathway. been to the degradation of the cell regulator in a proteasome-dependent K. Y. J. Nature. 1999; Scholar). However, the role of in the degradation is The protein interacts with and the budding yeast anaphase regulator for degradation through the Y. Curr. Biol. 2001; Scholar). Similarly, been well that the degradation of T. D. J. Biol. Chem. 2001; Scholar). In this is that as the the of S. J. Biol. Chem. 2001; Scholar). The that AIP also could Aurora-A kinase specifically through an as to is for Aurora-A degradation. AIP sequence not similarity to proteins M. Biophys. Mol. Biol. 1999; Scholar) or proteins S. M. M. N. K. J. Biol. Chem. 2001; Scholar), which roles in and the the of degradation in cells AIP the that AIP does not the in a The interaction of AIP with Aurora-A kinase as well as the essential of the interaction for the degradation of Aurora-A such as AIP Aurora-A kinase for destabilization or kinase interaction the in the Aurora-A kinase degradation pathway. is that Aurora-A kinase is degradation by K. Mihara H. Y. A. Tanaka H. Yasuda H. K. T. Scholar), to be that AIP plays a role in the of Aurora-A been that which is of interacts with human Aurora-A F.M. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar). However, the of Aurora-A for degradation also to be from its role in destabilization of Aurora-A kinase the function of AIP is to be The results to the that AIP is a ubiquitously expressed nuclear be to AIP is the for Aurora-A degradation. Other to be include the interaction AIP and Aurora-A and at which of cell Aurora-A degradation a negative regulator of Aurora-A, a potential there is a that down-regulation of AIP could a role in are to these In the in this a novel negative regulator of Aurora-A the function of AIP as well as the of the molecular involved in the destabilization of Aurora-A be the in this the degradation of Aurora-A by AIP with the to the of the Aurora-A AIP could therefore be a potential target gene for in the for the expression