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Aurora kinases in solely estrogen-in...

University of Kansas., Pharmacology, Toxicology & Therapeutics.

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Aurora kinases in solely estrogen-induced oncogenesis: Relation to centrosome amplification and chromosomal instability.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Aurora kinases in solely estrogen-induced oncogenesis: Relation to centrosome amplification and chromosomal instability./
Author:	Hontz, Adrianne Elizabeth.
Description:	180 p.
Notes:	Adviser: Jonathan J. Li.
Contained By:	Dissertation Abstracts International69-08B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3323390
ISBN:	9780549762713

Aurora kinases in solely estrogen-induced oncogenesis: Relation to centrosome amplification and chromosomal instability.
Hontz, Adrianne Elizabeth.

Aurora kinases in solely estrogen-induced oncogenesis: Relation to centrosome amplification and chromosomal instability. - 180 p.

Adviser: Jonathan J. Li.

Thesis (Ph.D.)--University of Kansas, 2008.

Persistent Aurora (Aur) A and B over-expression, centrosome amplification (CA), chromosomal instability (CIN) and aneuploidy invariably occur together in a vast majority of human neoplasms. These molecular changes are frequently found (>80%) in human sporadic ductal carcinoma in situ (DCIS) and in primary invasive ductal breast cancers (IDBC). In solely 17beta-estradiol (E2)-induced mammary tumors in ACI rats, Li et al. have previously shown AurA protein over-expression, CA, CIN and aneuploidy (Li et al., 2004). AurA and B, mitotic kinases involved in controlling proper cell division, are modulated by cell cycle progression. Their over-expression is implicated in the deregulation of chromosomal duplication/segregation, and cytokinesis leading to CA, CIN and aneuploidy. To determine whether the over-expression of Aur kinases is a common feature of E2-induced oncogenesis, AurA and B expression were examined in the Syrian hamster tumors of the kidney. Western blot analysis of the E2-induced Syrian hamster tumors of the kidney revealed that both AurA and B protein expression was markedly increased when compared to cholesterol-treated controls. Moreover, immunohistochemistry revealed that this increase in AurA and B expression was specifically localized to E2-induced tumor cells. Using an in vitro kinase assay, a significant increase in AurA kinase activity was detected in these tumors of the kidney and a significant increase in AurA mRNA levels was detected as measured by real-time PCR. The over-expression of both kinases was markedly reduced in E2-induced tumor-bearing hamsters subjected to either a 10-day E2-withdrawal period or treated for a similar period with Tamoxifen citrate (Tx) plus E2, when compared to tumors of the kidney from hamsters treated with E2 alone. These results indicate that both AurA and B are under estrogen control mediated by estrogen receptor alpha (ERalpha). Additionally, examination of centrin and gamma-tubulin expression in Syrian hamster tumors of the kidney indicates an increase in centrosome number and size, a characteristic of CA. The AurA expression was co-localized to isolated amplified tumor centrosomes, identified by their high levels of centrin and gamma-tubulin expression. CIN and aneuploidy in Syrian hamster tumors of the kidney has previously been demonstrated (Papa et al., 2003). In order to assess, during E2-induced oncogenesis, whether the over-expression of AurA and B contributes to the deregulation of the centrosome cycle via their specific protein substrates, we analyzed the protein expression of centrin, histone H3, PP1 and TPX2, all of which were significantly over-expressed in Syrian hamster tumors of the kidney and in ACI rat mammary gland tumors. Additionally, the expression of MDM2, which regulates the tumor suppressor gene p53, and p53 protein, an AurA substrate, were examined in Syrian hamster tumors of the kidney and in ACI rat mammary gland tumors. MDM2 expression was significantly increased in both Syrian hamster tumors of the kidney and in ACI rat mammary gland tumors at the protein and mRNA level, and estrogen modulation studies showed that MDM2 protein expression is either directly or indirectly controlled by E2. Binding studies show that MDM2 is bound to p53wt. MDM2-p53wt binding was inhibited in Syrian hamster tumors of the kidney after treatment with the small molecule inhibitor RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis). In E2-induced Syrian hamster tumors of the kidney, Western blot analysis revealed that RITA treatment led to a significant increase in p53wt protein expression when compared to untreated tumor samples. In addition, RITA treatment led to the increased expression of Bax, a downstream target gene of p53, which promotes apoptosis. These data suggest that Aur kinase over-expression, induced by estrogens, may interfere with bipolar spindle formation and chromosome segregation, leading to CA, CIN and aneuploidy, thus supporting the concept that AurA over-expression and CA are causative events, induced by estrogen, that lead to tumor development. The overexpression of MDM2, in tandem with AurA, indicates a close relationship between these two entities in fostering CA, CIN, aneuploidy and tumor development, defining events of E2-driven oncogenesis.

ISBN: 9780549762713Subjects--Topical Terms:

1017719
Biology, Molecular.

Aurora kinases in solely estrogen-induced oncogenesis: Relation to centrosome amplification and chromosomal instability.
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035 $a (UMI)AAI3323390
035 $a AAI3323390
040 $a UMI $c UMI
100 1 $a Hontz, Adrianne Elizabeth. $3 1025277
245 1 0 $a Aurora kinases in solely estrogen-induced oncogenesis: Relation to centrosome amplification and chromosomal instability.
300 $a 180 p.
500 $a Adviser: Jonathan J. Li.
500 $a Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4681.
502 $a Thesis (Ph.D.)--University of Kansas, 2008.
520 $a Persistent Aurora (Aur) A and B over-expression, centrosome amplification (CA), chromosomal instability (CIN) and aneuploidy invariably occur together in a vast majority of human neoplasms. These molecular changes are frequently found (>80%) in human sporadic ductal carcinoma in situ (DCIS) and in primary invasive ductal breast cancers (IDBC). In solely 17beta-estradiol (E2)-induced mammary tumors in ACI rats, Li et al. have previously shown AurA protein over-expression, CA, CIN and aneuploidy (Li et al., 2004). AurA and B, mitotic kinases involved in controlling proper cell division, are modulated by cell cycle progression. Their over-expression is implicated in the deregulation of chromosomal duplication/segregation, and cytokinesis leading to CA, CIN and aneuploidy. To determine whether the over-expression of Aur kinases is a common feature of E2-induced oncogenesis, AurA and B expression were examined in the Syrian hamster tumors of the kidney. Western blot analysis of the E2-induced Syrian hamster tumors of the kidney revealed that both AurA and B protein expression was markedly increased when compared to cholesterol-treated controls. Moreover, immunohistochemistry revealed that this increase in AurA and B expression was specifically localized to E2-induced tumor cells. Using an in vitro kinase assay, a significant increase in AurA kinase activity was detected in these tumors of the kidney and a significant increase in AurA mRNA levels was detected as measured by real-time PCR. The over-expression of both kinases was markedly reduced in E2-induced tumor-bearing hamsters subjected to either a 10-day E2-withdrawal period or treated for a similar period with Tamoxifen citrate (Tx) plus E2, when compared to tumors of the kidney from hamsters treated with E2 alone. These results indicate that both AurA and B are under estrogen control mediated by estrogen receptor alpha (ERalpha). Additionally, examination of centrin and gamma-tubulin expression in Syrian hamster tumors of the kidney indicates an increase in centrosome number and size, a characteristic of CA. The AurA expression was co-localized to isolated amplified tumor centrosomes, identified by their high levels of centrin and gamma-tubulin expression. CIN and aneuploidy in Syrian hamster tumors of the kidney has previously been demonstrated (Papa et al., 2003). In order to assess, during E2-induced oncogenesis, whether the over-expression of AurA and B contributes to the deregulation of the centrosome cycle via their specific protein substrates, we analyzed the protein expression of centrin, histone H3, PP1 and TPX2, all of which were significantly over-expressed in Syrian hamster tumors of the kidney and in ACI rat mammary gland tumors. Additionally, the expression of MDM2, which regulates the tumor suppressor gene p53, and p53 protein, an AurA substrate, were examined in Syrian hamster tumors of the kidney and in ACI rat mammary gland tumors. MDM2 expression was significantly increased in both Syrian hamster tumors of the kidney and in ACI rat mammary gland tumors at the protein and mRNA level, and estrogen modulation studies showed that MDM2 protein expression is either directly or indirectly controlled by E2. Binding studies show that MDM2 is bound to p53wt. MDM2-p53wt binding was inhibited in Syrian hamster tumors of the kidney after treatment with the small molecule inhibitor RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis). In E2-induced Syrian hamster tumors of the kidney, Western blot analysis revealed that RITA treatment led to a significant increase in p53wt protein expression when compared to untreated tumor samples. In addition, RITA treatment led to the increased expression of Bax, a downstream target gene of p53, which promotes apoptosis. These data suggest that Aur kinase over-expression, induced by estrogens, may interfere with bipolar spindle formation and chromosome segregation, leading to CA, CIN and aneuploidy, thus supporting the concept that AurA over-expression and CA are causative events, induced by estrogen, that lead to tumor development. The overexpression of MDM2, in tandem with AurA, indicates a close relationship between these two entities in fostering CA, CIN, aneuploidy and tumor development, defining events of E2-driven oncogenesis.
590 $a School code: 0099.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Oncology. $3 1018566
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0307
690 $a 0419
690 $a 0992
710 2 $a University of Kansas. $b Pharmacology, Toxicology & Therapeutics. $3 1025276
773 0 $t Dissertation Abstracts International $g 69-08B.
790 $a 0099
790 1 0 $a Enna, S. J. $e committee member
790 1 0 $a Li, Jonathan J., $e advisor
790 1 0 $a Pazdernik, Thomas $e committee member
790 1 0 $a Robertson, John $e committee member
790 1 0 $a Tawfik, Ossama $e committee member
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3323390