Aurora-A in cell mitosis role and relationship with tumor
Deviations during mitosis can cause centrosome amplification, chromosomal abnormalities and aneuploidy separation, which leads to genomic instability, causing tumors. To enable sister chromatid and other cellular components can be evenly into the daughter cells, requires a series of reversible protein phosphorylation, which includes Aurora kinase family [1]. Aurora-A belongs to Aurora kinase family is centrosome-associated kinase in cell mitosis plays an important role as it relates to a variety of malignancies, so the cause of many researchers. Clarify the Aurora-A during mitosis role will contribute to a deep understanding of Aurora-A-induced molecular mechanisms of tumorigenesis and to provide a new target for cancer therapy.
1 Aurora kinase family overview
Aurora kinase family is present in eukaryotic cells, involved in the regulation of mitosis of a class of serine - threonine kinase. Mammalian cells so far found three Aurora family members, namely: Aurora-A (Aurora2), Aurora-B (Aurora1), Aurora-C (Aurora3) [1]. Aurora kinase family is highly conserved in the structure of [2], the primary structure of the protein contains two domains, the variable region and the catalytic domain of human Aurora protein primary structure of three-member family series consistency greater than 55% , mostly concentrated in the C-terminal catalytic domain, and have the activation loop and degradation box. Although all three of the amino acid sequence of human Aurora kinases have great consistency, but they differ intracellular localization. Aurora-A in early S located in the centrosome replication and spindle poles until after mitotic exit, located in the vicinity of daughter nuclei [1]. Aurora-B is a chromosomal protein passing, targeted at early mitosis centromeric region, the later transferred to the spindle intermediate zone, culminating in cytokinesis focused on intermediates, this positioning makes the Aurora-B have a moderating kinetochore function is to correct chromosome alignment and separation, adjusting spindle checkpoint and cytokinesis required [3]. Aurora-C is a chromosomal passer protein [4], and Aurora-B, inner centromere protein and survivin and other passing protein, as in mitotic prophase and metaphase were located in condensation of chromosomes and centromere on the late shift to the spindle in the middle zone, cytokinesis centrosome positioning in place, its function and Aurora-B complement each other to meet the mitotic process needs. Aurora kinase family therefore different subcellular localization and their respective functions are intertwined, they are strictly intracellular space and time control, involved in the regulation of centrosome maturation, proper chromosome separation and cell division.
2 Aurora-A structure
The earliest human Aurora-A was detected in tissues from breast cancer, known as BTAK, aka Aurora2, AIK1, STK15, STK6, HsAIRK1 etc. [5]. Aurora-A from the 403 amino acids, protein primary structure contains two domains, one variable region, a catalytic zone. In the C-terminal catalytic domain amino acid sequence is highly conserved catalytic region and degradation boxes containing the activation loop, the activation loop Aurora-A kinase activity in regulation of degradation in box D-box degradation of Aurora-A kinase. In the N-terminal variable region, this region contains three box, they Aurora-A intracellular localization and identification, with the centrosome associated protein, wherein the A-box also responsible for the degradation of active D-box function [2] .
3 Aurora-A cyclical changes
Aurora-A kinase in the cell cycle dependent expression and distribution of presents. Its mRNA and protein levels in the G1 and S phase lowest gradually increased from G2 phase, in G2 / M phase increased to peak, M decreased rapidly after the end of the kinase activity in early mitosis maximum [6]. Aurora-A cyclical dynamic intracellular distribution: G2 of Aurora-A with the centrosome replication toward cell poles. In early mitosis, Aurora-A at the poles gradually close, and accompanied by the nuclear membrane thickening and retraction. With the disintegration of the nuclear membrane disappears, Aurora-A rapid increase and into spindle structure, located in the center and near the body area of ??microtubules. Post positioned in the vicinity of the center is reduced, while a small part appears in the middle area. Late and cytokinesis With the gradual degradation of Aurora-A, the majority can not be detected until the G2 phase of Aurora-A and re-distributed to the daughter nuclei near [7].
4 Aurora-A during mitosis role
4.1 Aurora-A and the center of the separation and mature
Centrosome as a cell microtubule organizing center, and its important function is to constitute a mitotic spindle in cell interphase microtubules regulate the quantity, stability, polarity and spatial distribution; in mitosis, centrosome establish bipolar spindle, ensure the symmetry of the process of cell division and bipolar, and this feature of chromosome separation precision is required.
Centrosome in G1 / S phase or early S start copying, to the S end of the formation of two unseparated centrosome, Aurora-A to the centrosome positioning at this time, stop it copied again and to promote its separation and mature, which When centrosome duplication has been completed, therefore, Aurora-A is not directly involved in centrosome duplication. Until the G1 phase of Aurora-A re-distributed to the degradation daughter nuclei near the central body can be carried out before the next replication, indicating Aurora-A only centrosome replication in a cell cycle 1 [6].
Aurora-A to the center of the separation is very important. Studies have shown that the use of RNAi technology interference in C. elegans embryos Aurora-A was found in the nuclear membrane rupture before the normal centrosome separation, but in the nuclear membrane rupture, centrosome separation together again, indicating that Aurora-A separation of the central body is not necessary to start, while the separation is essential to the maintenance of [8]. The results also show that when Drosophila Aurora-A mutation will cause abnormal centrosome separation, causing monopolar spindle [9].
Centrosome replication and separation experienced also requires a process of maturation, then we must raise a number of proteins to the central body, in order to ensure the normal mitosis. Through the fruit flies, nematodes found in early mitosis, ?-tubulin and Two centrioles surrounding material - D-TACC and MSPS Aurora-A-dependent manner gathered centrosome, where D-TACC a centrosome protein, from the centrosome and microtubule stabilizing role; MSPS is a microtubule-associated protein in maintaining the integrity of the spindle play an important role. Aurora-A to D-TACC phosphorylation of the microtubule binding protein complex formation MSPS/XMAP215 and promote their aggregation to the central body, the central body of stable microtubules [8,10,11].
4.2 Aurora-A and spindle assembly
Spindle microtubules pull chromosomes during cell division to cell poles, so that each daughter cell has a complete chromosomes. Aurora-A in the establishment and maintenance of a bipolar spindle plays a key role in inhibition of Aurora-A activity, can lead to the formation of spindle pole, while the bipolar spindle proper chromosome separation is provided [12]. Another study shows that in the absence of Aurora-A in human tumor cells, although the formation of a bipolar spindle, but the chromosomes are arranged to the equatorial plane can not [13].
Aurora-A kinase phosphorylation after having activity. In Xenopus egg extracts found, Aurora-A phosphorylation and activation by Ran-GTP-TPX2 pathway is activated, Ran-GTP activation, stimulation TPX2 from importin-a and importin-ß release, Aurora- after combination of A and TPX2 phosphorylated Aurora-A and to help locate the center of the vicinity of the micro tube, and the Aurora-A TPX2 when overexpressed can lead to inconsistent spindle assembly and chromosome segregation errors [14].
4.3 Aurora-A and G2 / M phase checkpoint
There are two key cell cycle turning point: G1 / S phase and G2 / M phase. G2 / M phase arrest of the cell's self-protective reaction mechanisms to provide time for cells to repair damaged DNA. If the repair is successful, the cells can enter mitosis, whereas cells into apoptosis phase. Aurora-A mainly in the G2 / M phase is activated, it can enter mitosis cells play a very important role. MARUMOTO, etc. [15] The anti-Aurora-A antibodies injected into G2 late Hela cells, the cells enter mitosis delay, but when overexpressed Aurora-A, can be canceled due DNA damage caused by the G2 / M phase resistance stagnation, the cells escape the G2 / M phase checkpoint, a direct entry into mitosis, resulting in chromosomal instability, indicating that Aurora-A participates in G2 / M phase checkpoint regulation.
5 Aurora-A and Cancer
5.1 Aurora-A gene amplification at 20q13
Human Aurora-A gene located on chromosome 20q13, this region are present in a number of malignant tumors gene amplification [16]. In breast cancer cell lines, 20q11 ~ q13 region amplification exists in 40% of cancer cells, and 20q13 region was amplified and over-expressed breast cancer patients with poor prognosis [17]. In gastric cancer after using FISH analysis, approximately 47% of the patients had 20q13 amplification region, including four cases (5%) highly amplified, 11 cases (15%) with moderate amplification, as well as 19 cases (28 %) Low amplification [18]. In primary colon cancer, 52% of patients in the region 20q13 amplification [16]. The evidence suggests that, Aurora-A is a clinically important oncogene.
5.2 Aurora-A mRNA and protein levels in overexpression
Usually in normal human tissues, Aurora-A is only a few cells in the presence of active proliferation of highly expressed organ, such as testis, thymus and fetal liver, but it is highly expressed in other tissues, they may contribute to tumorigenesis [19 ]. Previous studies have found that, Aurora-A in breast cancer, prostate cancer, bladder cancer, ovarian cancer, pancreatic cancer and other tumors in both highly expressed, and the Aurora-A is mainly distributed in the cytoplasm, is not limited to the central body [20].
5.3 Aurora-A with aneuploidy and centrosome disorders
In part or whole chromosomes obtained or lost characterized by aneuploidy can lead to genomic instability, thereby promoting tumorigenesis. It has been reported aneuploidy could be used as indicators of tumor progression and prognosis [21,22]. In gastric cancer and malignant papillary thyroid cancer, aneuploidy is a sign of metastasis and poor prognosis. About Aurora-A and the relationship between aneuploidy, studies have found that overexpression of Aurora-A and aneuploidy in gastric cancer occur simultaneously, and there is Aurora-A gene amplification and overexpression of clinical specimens have aneuploidy body and the characteristics of poor prognosis [23].
Centrosome amplification occurs when other anomalies that can lead to erroneous spindle assembly and chromosome segregation, the formation of aneuploidy, in almost all tumors and tumor cell lines were found in centrosome abnormalities [24]. Aurora-A as a centrosome-associated kinase, as it can lead to overexpression of centrosome amplification, chromosomal instability and malignant transformation of cells [25]. These are tips Aurora-A overexpression and centrosome abnormalities and aneuploidy appeared in tumor occurrence and development are inherently tied, so Aurora-A during mitosis in the regulation may be the trigger tumor one of the reasons .
5.4 Aurora-A and p53
Wild-type p53 (wt-p53) protein in maintaining genome stability also play an important role. wt-p53 during mitosis plays an important checkpoint role, a part of p53 was found in mitosis distributed in the centrosome, while wt-p53 down, deletions or mutations lead to centrosome amplification and genomic instability, which Aurora-A overexpression induced similar results [26,27].
Reported in the literature, wt-p53 protein Aurora-A plays a negative regulatory role [27], transcriptional activation in cells with non-dependent manner in direct binding of the N-terminus of Aurora-A and inhibits its activity to prevent over-expression of Aurora-A induced centrosome amplification and cell transformation; hand, Aurora-A highly activated and inhibit wt-p53 mediated negative regulation, because the Aurora-A of Ser315 phosphorylation of p53, thereby promoting media Mdm2 mediated p53 degradation through the ubiquitin pathway, but also on Ser215 phosphorylation of p53, inhibition of p53 transcriptional activity, and finally to loss of normal p53 function [28,29]. These findings suggest that Aurora-A induced tumors second reason is that it interacts with a number of substrate proteins, apoptosis and division affect the balance between over-expression or excessive activation of Aurora-A will break intracellular Aurora-A -p53 balance, resulting in malignant cell proliferation.
5.5 Aurora-A and c-myc
Aurora-A in the play a pivotal role in neoplastic transformation. Recent studies have found HIOSE118 ovarian epithelial cells and mammary epithelial cells MCF-10A high expression of Aurora-A can be increased c-myc, and through human telomerase reverse transcriptase (hTERT) promoter binding sites of c-myc-induced side granulocyte activity, RNAi interference c-myc, you can weaken Aurora-A induced expression of hTERT and telomerase activity [30]. This finding provides another malignant transformation molecular mechanisms that Aurora-A through upregulation induced c-myc and telomerase activity.
6 Prospects
Aurora-A kinase as a center-related, and many proteins that interact through phosphorylation is involved in cell mitosis, when it is over-expressed, causes centrosome amplification, induce cell transformation. As Aurora-A and the occurrence of cancer, the gene encoding it is also considered a novel oncogene, therefore, Aurora-A may become a target for cancer therapy. Currently, there are three kinds of literature have reported small molecule Aurora-A kinase inhibitors, which were ZM447439, MLN8054 and VX-680 [31,32]. They have found that in vitro anti-tumor activity, which could become the future direction of anti-tumor drug development.
1 Aurora kinase family overview
Aurora kinase family is present in eukaryotic cells, involved in the regulation of mitosis of a class of serine - threonine kinase. Mammalian cells so far found three Aurora family members, namely: Aurora-A (Aurora2), Aurora-B (Aurora1), Aurora-C (Aurora3) [1]. Aurora kinase family is highly conserved in the structure of [2], the primary structure of the protein contains two domains, the variable region and the catalytic domain of human Aurora protein primary structure of three-member family series consistency greater than 55% , mostly concentrated in the C-terminal catalytic domain, and have the activation loop and degradation box. Although all three of the amino acid sequence of human Aurora kinases have great consistency, but they differ intracellular localization. Aurora-A in early S located in the centrosome replication and spindle poles until after mitotic exit, located in the vicinity of daughter nuclei [1]. Aurora-B is a chromosomal protein passing, targeted at early mitosis centromeric region, the later transferred to the spindle intermediate zone, culminating in cytokinesis focused on intermediates, this positioning makes the Aurora-B have a moderating kinetochore function is to correct chromosome alignment and separation, adjusting spindle checkpoint and cytokinesis required [3]. Aurora-C is a chromosomal passer protein [4], and Aurora-B, inner centromere protein and survivin and other passing protein, as in mitotic prophase and metaphase were located in condensation of chromosomes and centromere on the late shift to the spindle in the middle zone, cytokinesis centrosome positioning in place, its function and Aurora-B complement each other to meet the mitotic process needs. Aurora kinase family therefore different subcellular localization and their respective functions are intertwined, they are strictly intracellular space and time control, involved in the regulation of centrosome maturation, proper chromosome separation and cell division.
2 Aurora-A structure
The earliest human Aurora-A was detected in tissues from breast cancer, known as BTAK, aka Aurora2, AIK1, STK15, STK6, HsAIRK1 etc. [5]. Aurora-A from the 403 amino acids, protein primary structure contains two domains, one variable region, a catalytic zone. In the C-terminal catalytic domain amino acid sequence is highly conserved catalytic region and degradation boxes containing the activation loop, the activation loop Aurora-A kinase activity in regulation of degradation in box D-box degradation of Aurora-A kinase. In the N-terminal variable region, this region contains three box, they Aurora-A intracellular localization and identification, with the centrosome associated protein, wherein the A-box also responsible for the degradation of active D-box function [2] .
3 Aurora-A cyclical changes
Aurora-A kinase in the cell cycle dependent expression and distribution of presents. Its mRNA and protein levels in the G1 and S phase lowest gradually increased from G2 phase, in G2 / M phase increased to peak, M decreased rapidly after the end of the kinase activity in early mitosis maximum [6]. Aurora-A cyclical dynamic intracellular distribution: G2 of Aurora-A with the centrosome replication toward cell poles. In early mitosis, Aurora-A at the poles gradually close, and accompanied by the nuclear membrane thickening and retraction. With the disintegration of the nuclear membrane disappears, Aurora-A rapid increase and into spindle structure, located in the center and near the body area of ??microtubules. Post positioned in the vicinity of the center is reduced, while a small part appears in the middle area. Late and cytokinesis With the gradual degradation of Aurora-A, the majority can not be detected until the G2 phase of Aurora-A and re-distributed to the daughter nuclei near [7].
4 Aurora-A during mitosis role
4.1 Aurora-A and the center of the separation and mature
Centrosome as a cell microtubule organizing center, and its important function is to constitute a mitotic spindle in cell interphase microtubules regulate the quantity, stability, polarity and spatial distribution; in mitosis, centrosome establish bipolar spindle, ensure the symmetry of the process of cell division and bipolar, and this feature of chromosome separation precision is required.
Centrosome in G1 / S phase or early S start copying, to the S end of the formation of two unseparated centrosome, Aurora-A to the centrosome positioning at this time, stop it copied again and to promote its separation and mature, which When centrosome duplication has been completed, therefore, Aurora-A is not directly involved in centrosome duplication. Until the G1 phase of Aurora-A re-distributed to the degradation daughter nuclei near the central body can be carried out before the next replication, indicating Aurora-A only centrosome replication in a cell cycle 1 [6].
Aurora-A to the center of the separation is very important. Studies have shown that the use of RNAi technology interference in C. elegans embryos Aurora-A was found in the nuclear membrane rupture before the normal centrosome separation, but in the nuclear membrane rupture, centrosome separation together again, indicating that Aurora-A separation of the central body is not necessary to start, while the separation is essential to the maintenance of [8]. The results also show that when Drosophila Aurora-A mutation will cause abnormal centrosome separation, causing monopolar spindle [9].
Centrosome replication and separation experienced also requires a process of maturation, then we must raise a number of proteins to the central body, in order to ensure the normal mitosis. Through the fruit flies, nematodes found in early mitosis, ?-tubulin and Two centrioles surrounding material - D-TACC and MSPS Aurora-A-dependent manner gathered centrosome, where D-TACC a centrosome protein, from the centrosome and microtubule stabilizing role; MSPS is a microtubule-associated protein in maintaining the integrity of the spindle play an important role. Aurora-A to D-TACC phosphorylation of the microtubule binding protein complex formation MSPS/XMAP215 and promote their aggregation to the central body, the central body of stable microtubules [8,10,11].
4.2 Aurora-A and spindle assembly
Spindle microtubules pull chromosomes during cell division to cell poles, so that each daughter cell has a complete chromosomes. Aurora-A in the establishment and maintenance of a bipolar spindle plays a key role in inhibition of Aurora-A activity, can lead to the formation of spindle pole, while the bipolar spindle proper chromosome separation is provided [12]. Another study shows that in the absence of Aurora-A in human tumor cells, although the formation of a bipolar spindle, but the chromosomes are arranged to the equatorial plane can not [13].
Aurora-A kinase phosphorylation after having activity. In Xenopus egg extracts found, Aurora-A phosphorylation and activation by Ran-GTP-TPX2 pathway is activated, Ran-GTP activation, stimulation TPX2 from importin-a and importin-ß release, Aurora- after combination of A and TPX2 phosphorylated Aurora-A and to help locate the center of the vicinity of the micro tube, and the Aurora-A TPX2 when overexpressed can lead to inconsistent spindle assembly and chromosome segregation errors [14].
4.3 Aurora-A and G2 / M phase checkpoint
There are two key cell cycle turning point: G1 / S phase and G2 / M phase. G2 / M phase arrest of the cell's self-protective reaction mechanisms to provide time for cells to repair damaged DNA. If the repair is successful, the cells can enter mitosis, whereas cells into apoptosis phase. Aurora-A mainly in the G2 / M phase is activated, it can enter mitosis cells play a very important role. MARUMOTO, etc. [15] The anti-Aurora-A antibodies injected into G2 late Hela cells, the cells enter mitosis delay, but when overexpressed Aurora-A, can be canceled due DNA damage caused by the G2 / M phase resistance stagnation, the cells escape the G2 / M phase checkpoint, a direct entry into mitosis, resulting in chromosomal instability, indicating that Aurora-A participates in G2 / M phase checkpoint regulation.
5 Aurora-A and Cancer
5.1 Aurora-A gene amplification at 20q13
Human Aurora-A gene located on chromosome 20q13, this region are present in a number of malignant tumors gene amplification [16]. In breast cancer cell lines, 20q11 ~ q13 region amplification exists in 40% of cancer cells, and 20q13 region was amplified and over-expressed breast cancer patients with poor prognosis [17]. In gastric cancer after using FISH analysis, approximately 47% of the patients had 20q13 amplification region, including four cases (5%) highly amplified, 11 cases (15%) with moderate amplification, as well as 19 cases (28 %) Low amplification [18]. In primary colon cancer, 52% of patients in the region 20q13 amplification [16]. The evidence suggests that, Aurora-A is a clinically important oncogene.
5.2 Aurora-A mRNA and protein levels in overexpression
Usually in normal human tissues, Aurora-A is only a few cells in the presence of active proliferation of highly expressed organ, such as testis, thymus and fetal liver, but it is highly expressed in other tissues, they may contribute to tumorigenesis [19 ]. Previous studies have found that, Aurora-A in breast cancer, prostate cancer, bladder cancer, ovarian cancer, pancreatic cancer and other tumors in both highly expressed, and the Aurora-A is mainly distributed in the cytoplasm, is not limited to the central body [20].
5.3 Aurora-A with aneuploidy and centrosome disorders
In part or whole chromosomes obtained or lost characterized by aneuploidy can lead to genomic instability, thereby promoting tumorigenesis. It has been reported aneuploidy could be used as indicators of tumor progression and prognosis [21,22]. In gastric cancer and malignant papillary thyroid cancer, aneuploidy is a sign of metastasis and poor prognosis. About Aurora-A and the relationship between aneuploidy, studies have found that overexpression of Aurora-A and aneuploidy in gastric cancer occur simultaneously, and there is Aurora-A gene amplification and overexpression of clinical specimens have aneuploidy body and the characteristics of poor prognosis [23].
Centrosome amplification occurs when other anomalies that can lead to erroneous spindle assembly and chromosome segregation, the formation of aneuploidy, in almost all tumors and tumor cell lines were found in centrosome abnormalities [24]. Aurora-A as a centrosome-associated kinase, as it can lead to overexpression of centrosome amplification, chromosomal instability and malignant transformation of cells [25]. These are tips Aurora-A overexpression and centrosome abnormalities and aneuploidy appeared in tumor occurrence and development are inherently tied, so Aurora-A during mitosis in the regulation may be the trigger tumor one of the reasons .
5.4 Aurora-A and p53
Wild-type p53 (wt-p53) protein in maintaining genome stability also play an important role. wt-p53 during mitosis plays an important checkpoint role, a part of p53 was found in mitosis distributed in the centrosome, while wt-p53 down, deletions or mutations lead to centrosome amplification and genomic instability, which Aurora-A overexpression induced similar results [26,27].
Reported in the literature, wt-p53 protein Aurora-A plays a negative regulatory role [27], transcriptional activation in cells with non-dependent manner in direct binding of the N-terminus of Aurora-A and inhibits its activity to prevent over-expression of Aurora-A induced centrosome amplification and cell transformation; hand, Aurora-A highly activated and inhibit wt-p53 mediated negative regulation, because the Aurora-A of Ser315 phosphorylation of p53, thereby promoting media Mdm2 mediated p53 degradation through the ubiquitin pathway, but also on Ser215 phosphorylation of p53, inhibition of p53 transcriptional activity, and finally to loss of normal p53 function [28,29]. These findings suggest that Aurora-A induced tumors second reason is that it interacts with a number of substrate proteins, apoptosis and division affect the balance between over-expression or excessive activation of Aurora-A will break intracellular Aurora-A -p53 balance, resulting in malignant cell proliferation.
5.5 Aurora-A and c-myc
Aurora-A in the play a pivotal role in neoplastic transformation. Recent studies have found HIOSE118 ovarian epithelial cells and mammary epithelial cells MCF-10A high expression of Aurora-A can be increased c-myc, and through human telomerase reverse transcriptase (hTERT) promoter binding sites of c-myc-induced side granulocyte activity, RNAi interference c-myc, you can weaken Aurora-A induced expression of hTERT and telomerase activity [30]. This finding provides another malignant transformation molecular mechanisms that Aurora-A through upregulation induced c-myc and telomerase activity.
6 Prospects
Aurora-A kinase as a center-related, and many proteins that interact through phosphorylation is involved in cell mitosis, when it is over-expressed, causes centrosome amplification, induce cell transformation. As Aurora-A and the occurrence of cancer, the gene encoding it is also considered a novel oncogene, therefore, Aurora-A may become a target for cancer therapy. Currently, there are three kinds of literature have reported small molecule Aurora-A kinase inhibitors, which were ZM447439, MLN8054 and VX-680 [31,32]. They have found that in vitro anti-tumor activity, which could become the future direction of anti-tumor drug development.
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