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Molecular and Cellular Biology, July 2002, p. 5235-5247, Vol. 22, No. 14
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.14.5235-5247.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Characterization of Mice Deficient in the Src Family Nonreceptor Tyrosine Kinase Frk/rak

Subhashini Chandrasekharan,^1,2, Ting Hu Qiu,² Nawal Alkharouf,² Kelly Brantley,² James B. Mitchell,³ and Edison T. Liu^2*

Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,¹ Section of Cell Signaling and Oncogenesis, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland 20877,² Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892³

Received 12 November 2001/ Returned for modification 14 January 2002/ Accepted 13 March 2002

Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Although developmental expression patterns and functional overexpression in vitro have associated these kinases with growth suppression and differentiation, their physiological functions remain largely unknown. We therefore generated mice carrying a null mutation in iyk, the mouse homolog of Frk/rak. We report here that frk/rak^-/- mice are viable, show similar growth rates to wild-type animals, and are fertile. Furthermore, a 2-year study of health and survival did not identify differences in the incidence and spectrum of spontaneous tumors or provide evidence of hyperplasias in frk/rak^-/- epithelial tissues. Histological analysis of organs failed to reveal any morphological changes in epithelial tissues that normally express high levels of Frk/rak. Ultrastructural analysis of intestinal enterocytes did not identify defects in brush border morphology or structural polarization, demonstrating that Frk/rak is dispensable for intestinal cytodifferentiation. Additionally, frk/rak-null mice do not display altered sensitivity to intestinal damage induced by ionizing radiation. cDNA microarray analysis revealed an increase in c-src expression and identified subtle changes in the expression of genes regulated by thyroid hormones. Significant decreases in the circulating levels of T3 but not T4 hormone are consistent with this observation and reminiscent of euthyroid sick syndrome, a stress-associated clinical condition.

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* Corresponding author. Present address: Genome Institute of Singapore, 1 Capricorn 05-01, Science Park II, Singapore 117528, Singapore. Phone: 65-68275212. Fax: 65-68275202. E-mail: gisliue{at}nus.edu.sg.

Present address: Department of Cystic Fibrosis and Pulmonary Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248.

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Molecular and Cellular Biology, July 2002, p. 5235-5247, Vol. 22, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.14.5235-5247.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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