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A role for the nuclear receptor PPAR...

Sarraf, Pasha.

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A role for the nuclear receptor PPARgamma in cancer.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	A role for the nuclear receptor PPARgamma in cancer./
Author:	Sarraf, Pasha.
Description:	139 p.
Notes:	Adviser: Bruce Spiegelman.
Contained By:	Dissertation Abstracts International63-04B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051281
ISBN:	0493658556

A role for the nuclear receptor PPARgamma in cancer.
Sarraf, Pasha.

A role for the nuclear receptor PPARgamma in cancer. - 139 p.

Adviser: Bruce Spiegelman.

Thesis (Ph.D.)--Harvard University, 2002.

Induction of terminal differentiation represents a promising therapeutic approach to certain human malignancies. The peroxisome proliferator-activated receptor-gamma (PPARγ) and the retinoid-X-receptor alpha (RXRα) form a heterodimeric complex that functions as a central regulator of adipocyte differentiation. The effects of PPARγ on cellular growth and differentiation, together with the availability of PPARγ ligands for therapeutic purposes provide a compelling rational for the study of this protein in cancer and its use as a target for differentiation therapy.

ISBN: 0493658556Subjects--Topical Terms:

1017686
Biology, Cell.

A role for the nuclear receptor PPARgamma in cancer.
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005 20110425
008 110425s2002 eng d
020 $a 0493658556
035 $a (UnM)AAI3051281
035 $a AAI3051281
040 $a UnM $c UnM
100 1 $a Sarraf, Pasha. $3 1251333
245 1 0 $a A role for the nuclear receptor PPARgamma in cancer.
300 $a 139 p.
500 $a Adviser: Bruce Spiegelman.
500 $a Source: Dissertation Abstracts International, Volume: 63-04, Section: B, page: 1652.
502 $a Thesis (Ph.D.)--Harvard University, 2002.
520 $a Induction of terminal differentiation represents a promising therapeutic approach to certain human malignancies. The peroxisome proliferator-activated receptor-gamma (PPARγ) and the retinoid-X-receptor alpha (RXRα) form a heterodimeric complex that functions as a central regulator of adipocyte differentiation. The effects of PPARγ on cellular growth and differentiation, together with the availability of PPARγ ligands for therapeutic purposes provide a compelling rational for the study of this protein in cancer and its use as a target for differentiation therapy.
520 $a PPARγ is present at significant levels in both primary and metastatic adenocarcinomas of the breast and colon. In cell lines derived from these tumors, activation of PPARγ through specific ligands leads to growth inhibition that is dose and time-dependent. Growth inhibition is accompanied by morphological and biochemical changes that are consistent with a more mature and differentiated phenotype. Some cells, which are derived from highly metastatic tumors, express high levels of PPARγ, but show little functional response to its ligands. In these cells, resistance is associated with elevated activity of MAP kinase, leading to the inhibition of PPARγ pathway by phosphorylation of this receptor. Blocking the activation of MAP kinase restores ligand responsiveness in these cells. Finally, transplantable tumors derived from human colon cancer cells show a significant reduction of growth when mice are treated with troglitazone, a PPARγ ligand.
520 $a To critically assess the role of PPARγ in colon cancer, a genetic analysis of PPARγ was undertaken. The screen of 55 sporadic colon cancers for PPARγ mutations led to the identification of 4 mutations. Each mutation greatly impaired the function of the protein. These data indicate that colon cancer in humans is associated with loss-of-function mutations of PPARγ.
520 $a Together these results suggest a novel role for PPARγ in epithelial biology. PPARγ appears to be critical in either determination or modulation of cellular differentiation and its maximal ligand activation is effective in both growth and tumor suppression. Epigenetic repression and loss-of-function mutations of PPARγ provide additional evidence for the importance of this receptor in tumor suppression. Differentiation therapy with PPARγ ligands may provide potential benefit to patients with cancer. More importantly these studies provide the biological rational and framework for the application of PPARγ ligands in cancer therapy, as monotherapy, as well as other approaches to cancer treatment including the use of PPARγ ligands for adjuvant therapy or in chemoprevention.
590 $a School code: 0084.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Oncology. $3 1018566
690 $a 0307
690 $a 0369
690 $a 0379
690 $a 0992
710 2 0 $a Harvard University. $3 528741
773 0 $t Dissertation Abstracts International $g 63-04B.
790 $a 0084
790 1 0 $a Spiegelman, Bruce, $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051281