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The role of the sonic hedgehog signa...

Hamm, Rebecca Lynn.

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The role of the sonic hedgehog signaling pathway in epidermal homeostasis.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	The role of the sonic hedgehog signaling pathway in epidermal homeostasis./
作者:	Hamm, Rebecca Lynn.
面頁冊數:	153 p.
附註:	Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1039.
Contained By:	Dissertation Abstracts International64-03B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3083493

The role of the sonic hedgehog signaling pathway in epidermal homeostasis.
Hamm, Rebecca Lynn.

The role of the sonic hedgehog signaling pathway in epidermal homeostasis. - 153 p.

Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1039.

Thesis (Ph.D.)--The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, 2003.

Non-melanoma skin cancer is the most frequently diagnosed malignancy in the United States of which basal cell carcinoma (BCC) accounts for 65%. It has recently been determined that deregulation of the sonic hedgehog (shh) pathway leads to the development of BCC. Shh, gli-1, gli-2 gli-3, ptc and smo are overexpressed in BCC and overexpression of these genes in the epidermis results in formation of BCC-like tumors. Despite these observations, the mechanisms by which the pathway controls epidermal homeostasis and the development of the malignant phentotype are unknown. This study assessed the role of the shh pathway in epidermal homeostasis through regulation of apoptosis and differentiation.Subjects--Topical Terms:

1017686
Biology, Cell.

The role of the sonic hedgehog signaling pathway in epidermal homeostasis.
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245 1 0 $a The role of the sonic hedgehog signaling pathway in epidermal homeostasis.
300 $a 153 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1039.
500 $a Supervisor: Timothy J. McDonnell.
502 $a Thesis (Ph.D.)--The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, 2003.
520 $a Non-melanoma skin cancer is the most frequently diagnosed malignancy in the United States of which basal cell carcinoma (BCC) accounts for 65%. It has recently been determined that deregulation of the sonic hedgehog (shh) pathway leads to the development of BCC. Shh, gli-1, gli-2 gli-3, ptc and smo are overexpressed in BCC and overexpression of these genes in the epidermis results in formation of BCC-like tumors. Despite these observations, the mechanisms by which the pathway controls epidermal homeostasis and the development of the malignant phentotype are unknown. This study assessed the role of the shh pathway in epidermal homeostasis through regulation of apoptosis and differentiation.
520 $a The anti-apoptotic protein, bcl-2 is overexpressed in BCC, however transcriptional regulators of bcl-2 in the epidermis are unknown. Transient transfection of primary keratinocytes with gli-1 resulted in an increase of bcl-2 expression. Database analysis revealed seven candidate gli binding sites on the bcl-2 promoter. Cotransfection of increasing amounts of gli-1 in keratinoycytes resulted in a corresponding dose-dependent increase in bcl-2 promoter luciferase activity. An N-terminal mutant of gli-3 inhibited gli-1 transactivation of the bcl-2 promoter. The region −428 to −420 was found to be important for gli-1 regulation through gel shift, luciferase assays and site-directed mutagenesis.
520 $a In order to assess the ability of the shh pathway to regulate keratinocyte differentiation, HaCaT keratinocytes overexpressing sonic hedgehog, were grown in organotypic raft culture. Overexpression of shh induced a basal cell phenotype compared to vector control, as evidenced by transmural staining of cytokeratin 14 and altered Ki67 staining. Shh also induced keratinocyte invasion into the underlying collagen. This was associated with increased phosphorylation of EGFR, jnk and raf and increased expression of c-jun, mmp-9 and Ki67. Interestingly, shh overexpression in HaCaTs did not induce the typical downstream effects of shh signaling, suggesting a gli-independent mechanism. Sonic hedgehog's ability to induce an invasive phenotype was found to be dependent on activation of the EGF pathway as inhibition of EGFR activity with AG1478 and c-225 was able to reduce the invasiveness of HaCaT shh keratinocytes, whereas treatment with EGF augmented the invasiveness of the HaCaT shh clones.
520 $a These studies reveal the importance of the sonic hedgehog pathway in epidermal homeostasis by regulation of apoptosis through bcl-2, and control of keratinocyte differentiation and invasion through activation of the EGF pathway. They further suggest potential mechanisms by which deregulation of the shh pathway may lead to the development of the malignant phenotype.
590 $a School code: 2034.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Oncology. $3 1018566
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710 2 0 $a The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences. $3 1251166
773 0 $t Dissertation Abstracts International $g 64-03B.
790 $a 2034
790 1 0 $a McDonnell, Timothy J., $e advisor
791 $a Ph.D.
792 $a 2003
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