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Serum and glucocorticoid-regulated k...

Gasser, Jessica Ann.

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Serum and glucocorticoid-regulated kinase signaling in breast cancer.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Serum and glucocorticoid-regulated kinase signaling in breast cancer./
作者:	Gasser, Jessica Ann.
面頁冊數:	182 p.
附註:	Source: Dissertation Abstracts International, Volume: 75-06(E), Section: B.
Contained By:	Dissertation Abstracts International75-06B(E).
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3611530
ISBN:	9781303724138

Serum and glucocorticoid-regulated kinase signaling in breast cancer.
Gasser, Jessica Ann.

Serum and glucocorticoid-regulated kinase signaling in breast cancer. - 182 p.

Source: Dissertation Abstracts International, Volume: 75-06(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2014.

This item is not available from ProQuest Dissertations & Theses.

Oncogenic activating mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI 3-K), are highly prevalent in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, though the mechanisms by which PI 3-K mediates tumorigenic signals in an Akt-independent manner remain obscure. My studies show that the serum and glucocorticoid-regulated kinases (SGKs) can function as effectors of PI 3-kinase and transduce signals to phenotypes associated with malignancy. We show that SGK3 is amplified in breast cancer and identify the mechanism by which SGK3 is activated downstream of PIK3CA, specifically through the catalytic activity of the phosphoinositide phosphatase INPP4B. Expression of INPP4B promotes SGK3 activation and in turn inhibits Akt phosphorylation. In breast cancer cell lines with elevated levels of INPP4B, SGK3 is required for proliferation in 3D and also for invasive migration. SGK3 phenotypes are in part mediated by phosphorylation of the substrate protein N-myc downstream regulated 1 (NDRG1), an established metastasis suppressor. The phosphorylation of NDRG1 leads to recruitment by F-box and WD repeat domain-containing 7 (FBW7), the substrate recognition domain of the Skp, Cullin, F-box containing (SCF) complex. Binding of Fbw7 to NDRG1 promotes its polyubiquitination and subsequent degradation by the 26S proteasome. By contrast, our studies also show that the related SGK1 isoform is polyubiquitinated by the functional E3 ubiquitin ligase Rictor-Cullin-1 complex, leading to SGK1 degradation. Proteasomal degradation of SGK1 by Rictor-Cullin-1is the first identified mTORC2-independent function of the Rictor protein. Moreover, the deregulation of SGK1 ubiquitination highlights a mechanism of SGK1 overexpression in breast cancers. Taken together, these findings highlight novel post-translational modifications of SGK isoforms converging on the theme of ubiquitination and degradation. Alterations in ubiquitination status lead to the deregulation of cellular phenotypes such as proliferation and migration. The data presented in this thesis also highlight a mechanism by which SGK isoforms transduce oncogenic PI3-kinase signaling in breast cancer. The oncogenic potential of SGK signaling is further emphasized by the aberrant expression levels of SGK1 and SGK3 in breast cancers.

ISBN: 9781303724138Subjects--Topical Terms:

3172791
Cellular biology.

Serum and glucocorticoid-regulated kinase signaling in breast cancer.
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520 $a Oncogenic activating mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI 3-K), are highly prevalent in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, though the mechanisms by which PI 3-K mediates tumorigenic signals in an Akt-independent manner remain obscure. My studies show that the serum and glucocorticoid-regulated kinases (SGKs) can function as effectors of PI 3-kinase and transduce signals to phenotypes associated with malignancy. We show that SGK3 is amplified in breast cancer and identify the mechanism by which SGK3 is activated downstream of PIK3CA, specifically through the catalytic activity of the phosphoinositide phosphatase INPP4B. Expression of INPP4B promotes SGK3 activation and in turn inhibits Akt phosphorylation. In breast cancer cell lines with elevated levels of INPP4B, SGK3 is required for proliferation in 3D and also for invasive migration. SGK3 phenotypes are in part mediated by phosphorylation of the substrate protein N-myc downstream regulated 1 (NDRG1), an established metastasis suppressor. The phosphorylation of NDRG1 leads to recruitment by F-box and WD repeat domain-containing 7 (FBW7), the substrate recognition domain of the Skp, Cullin, F-box containing (SCF) complex. Binding of Fbw7 to NDRG1 promotes its polyubiquitination and subsequent degradation by the 26S proteasome. By contrast, our studies also show that the related SGK1 isoform is polyubiquitinated by the functional E3 ubiquitin ligase Rictor-Cullin-1 complex, leading to SGK1 degradation. Proteasomal degradation of SGK1 by Rictor-Cullin-1is the first identified mTORC2-independent function of the Rictor protein. Moreover, the deregulation of SGK1 ubiquitination highlights a mechanism of SGK1 overexpression in breast cancers. Taken together, these findings highlight novel post-translational modifications of SGK isoforms converging on the theme of ubiquitination and degradation. Alterations in ubiquitination status lead to the deregulation of cellular phenotypes such as proliferation and migration. The data presented in this thesis also highlight a mechanism by which SGK isoforms transduce oncogenic PI3-kinase signaling in breast cancer. The oncogenic potential of SGK signaling is further emphasized by the aberrant expression levels of SGK1 and SGK3 in breast cancers.
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