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Regulation of the arginine/lysine tr...

Fernandez, James Michael.

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Regulation of the arginine/lysine transporter, cat-1, by cellular and nutritional stress.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Regulation of the arginine/lysine transporter, cat-1, by cellular and nutritional stress./
Author:	Fernandez, James Michael.
Description:	210 p.
Notes:	Adviser: Maria Hatzoglou.
Contained By:	Dissertation Abstracts International63-10B.
Subject:	Health Sciences, Nutrition. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3068085
ISBN:	0493874151

Regulation of the arginine/lysine transporter, cat-1, by cellular and nutritional stress.
Fernandez, James Michael.

Regulation of the arginine/lysine transporter, cat-1, by cellular and nutritional stress. - 210 p.

Adviser: Maria Hatzoglou.

Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 2002.

The cationic amino acid transporter, cat-1, facilitates the uptake of the essential amino acids arginine and lysine. Amino acid starvation causes accumulation and increased translation of cat-1 mRNA, resulting in increased protein levels and increased arginine uptake. In contrast to the cat-1 mRNA, the cap-dependent translation of most cellular mRNAs decreases during amino acid limitation. It is shown here that translation of the cat-1 mRNA during amino acid starvation is cap-independent. A bicistronic mRNA expression system was used to demonstrate the presence of an internal ribosomal entry sequence (IRES) within the 5<super>′</super> untranslated region of the cat-1 mRNA. This IRES causes an increase in translation under conditions of amino acid starvation. Here it is shown that cat-1 IRES-mediated translation during amino acid starvation depends on eIF2α phosphorylation. It is also shown that the IRES-mediated translation requires the translation of a 48 amino acid upstream-ORF present within the 5<super>′</super>-leader of the transporter mRNA. A model of an mRNA conformational change is presented here, suggesting remodeling of the cat1 mRNA upon eIF2α phosphorylation and translation of the uORF. This remodeling involves RNA-RNA interactions allowing for high IRES-mediated translation. This is the first example of a cellular IRES that undergoes mRNA rearrangement to allow for efficient internal initiation upon cellular stress. It is also shown that other stresses that cause the phosphorylation of the translation initiation factor eIF2α also cause an induction of cat-1 IRES-mediated translation. Comparing the regulation of IRES-mediated translation of known IRESs revealed that cellular stress can stimulate translation from some but not all cellular IRESs via a mechanism that requires the phosphorylation of eIF2α. Moreover, there are distinct translational control patterns for different cellular mRNAs that contain IRESs within their 5<super>′</super>-UTRs. These findings reveal a new aspect of mammalian gene expression and regulation that provides a cellular stress response; when the nutrient supply is limited, the activation of IRES-mediated translation of mammalian mRNAs results in the synthesis of proteins essential for cell survival.

ISBN: 0493874151Subjects--Topical Terms:

1017801
Health Sciences, Nutrition.

Regulation of the arginine/lysine transporter, cat-1, by cellular and nutritional stress.
LDR:03218nam 2200265 a 45 001 929405
005 20110427
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020 $a 0493874151
035 $a (UnM)AAI3068085
035 $a AAI3068085
040 $a UnM $c UnM
100 1 $a Fernandez, James Michael. $3 1252891
245 1 0 $a Regulation of the arginine/lysine transporter, cat-1, by cellular and nutritional stress.
300 $a 210 p.
500 $a Adviser: Maria Hatzoglou.
500 $a Source: Dissertation Abstracts International, Volume: 63-10, Section: B, page: 4601.
502 $a Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 2002.
520 $a The cationic amino acid transporter, cat-1, facilitates the uptake of the essential amino acids arginine and lysine. Amino acid starvation causes accumulation and increased translation of cat-1 mRNA, resulting in increased protein levels and increased arginine uptake. In contrast to the cat-1 mRNA, the cap-dependent translation of most cellular mRNAs decreases during amino acid limitation. It is shown here that translation of the cat-1 mRNA during amino acid starvation is cap-independent. A bicistronic mRNA expression system was used to demonstrate the presence of an internal ribosomal entry sequence (IRES) within the 5<super>′</super> untranslated region of the cat-1 mRNA. This IRES causes an increase in translation under conditions of amino acid starvation. Here it is shown that cat-1 IRES-mediated translation during amino acid starvation depends on eIF2α phosphorylation. It is also shown that the IRES-mediated translation requires the translation of a 48 amino acid upstream-ORF present within the 5<super>′</super>-leader of the transporter mRNA. A model of an mRNA conformational change is presented here, suggesting remodeling of the cat1 mRNA upon eIF2α phosphorylation and translation of the uORF. This remodeling involves RNA-RNA interactions allowing for high IRES-mediated translation. This is the first example of a cellular IRES that undergoes mRNA rearrangement to allow for efficient internal initiation upon cellular stress. It is also shown that other stresses that cause the phosphorylation of the translation initiation factor eIF2α also cause an induction of cat-1 IRES-mediated translation. Comparing the regulation of IRES-mediated translation of known IRESs revealed that cellular stress can stimulate translation from some but not all cellular IRESs via a mechanism that requires the phosphorylation of eIF2α. Moreover, there are distinct translational control patterns for different cellular mRNAs that contain IRESs within their 5<super>′</super>-UTRs. These findings reveal a new aspect of mammalian gene expression and regulation that provides a cellular stress response; when the nutrient supply is limited, the activation of IRES-mediated translation of mammalian mRNAs results in the synthesis of proteins essential for cell survival.
590 $a School code: 0499.
650 4 $a Health Sciences, Nutrition. $3 1017801
690 $a 0570
710 2 0 $a Case Western Reserve University (Health Sciences). $3 1250782
773 0 $t Dissertation Abstracts International $g 63-10B.
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790 1 0 $a Hatzoglou, Maria, $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3068085