HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Prabhakar, R. Articles by Wieczorek, D. F. Search for Related Content PubMed PubMed Citation Articles by Prabhakar, R. Articles by Wieczorek, D. F. Social Bookmarking                      What's this?

J Biol Chem, Vol. 274, Issue 41, 29558-29563, October 8, 1999

Rescue of High Expression -Tropomyosin Transgenic Mice by 5-Propyl-2-thiouracil
REGULATING THE -MYOSIN HEAVY CHAIN PROMOTER

Rethinasamy Prabhakar, Greg P. Boivin^§, Brian Hoit^¶, and David F. Wieczorek

From the Departments of  Molecular Genetics, Biochemistry, and Microbiology, ^§ Pathology and Laboratory Medicine, and ^¶ Internal Medicine, Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524

Tropomyosin is an essential component of the sarcomeric thin filament in striated muscle that participates in the regulation of muscle contraction through Ca²⁺-mediated activation. The two predominant tropomyosin isoforms expressed in striated muscle are - and -tropomyosin, which exhibit an 86% amino acid identity between themselves. Previous studies by our laboratory utilized a transgenic mouse system to overexpress -tropomyosin in the heart to address the functional differences between these two tropomyosin isoforms. Interestingly, when a high percentage of -tropomyosin replaces -tropomyosin in the hearts of transgenic mice, the mice die due to severe cardiac abnormalities. In this study, we have rescued these high expression -tropomyosin mice by turning off the -myosin heavy chain promoter, which is driving the -tropomyosin transgene. This down-regulation of the -myosin heavy chain promoter was accomplished by the administration of 5-propyl-2-thiouracil, which disrupts thyroid hormone synthesis and inhibits promoter activity through thyroid regulatory elements located in the 5'-flanking region of the promoter. Results show that as -tropomyosin expression is down-regulated, -tropomyosin expression is increased. Also, - and -myosin heavy chain expression is modified in response to the changes in thyroid hormone expression. Morphological analysis of these rescued mice show a moderate pathological phenotype, characterized by atrial myocytolysis; echocardiographic analyses demonstrate altered ventricular functions, such as peak filling rates and left ventricular fractional shortening. This is the first report demonstrating that transcriptional regulatory elements located within the -myosin heavy chain promoter can be manipulated to rescue potentially lethal phenotypes, such as high expression -tropomyosin transgenic mice.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				P. Gunning, G. O'neill, and E. Hardeman Tropomyosin-Based Regulation of the Actin Cytoskeleton in Time and Space Physiol Rev, January 1, 2008; 88(1): 1 - 35. [Abstract] [Full Text] [PDF]

				T. Miller, D. Szczesna, P. R. Housmans, J. Zhao, F. de Freitas, A. V. Gomes, L. Culbreath, J. McCue, Y. Wang, Y. Xu, et al. Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation J. Biol. Chem., February 2, 2001; 276(6): 3743 - 3755. [Abstract] [Full Text] [PDF]