Characterization of integrin beta6 and thrombospondin-1 double-null mice.
To identify overlapping and non-overlapping functions for TSP-1 and alphavbeta6, we crossed TSP-1-null and beta6-null mice and compared the phenotype of the double-null mice with those of wild-type and single-null mice. The double-null mice exhibited focal acute and organizing pneumonia that was more severe than the wild-type and single-null mice as well as a significantly higher incidence of inflammation in tissues other than the lung. The TSP-1-null and beta6-null mice exhibited a five to eight-fold increase in granulocyte recruitment to the lung three days after exposure to lipopolysaccharide. They also had abnormalities that were infrequently observed in the wild-type and single-null mice, including heart degeneration (8.35% in wild-type and 28.1% in double-null mice), hyperplasia of the glandular of the stomach (2.8% in wild-type and 21.1% in double-null mice) and endometrial hyperplasia (0% in wild-type and 38.5% in double-null females). Furthermore, the beta6-null and double-null mice displayed a significant elevation in benign and malignant cancers. Stomach papillomas, squamous cell carcinomas of the ear and stomach, and adenocarcinomas of the lungs, vagina/cervix and colon were observed with the highest frequency. These data demonstrate that TSP-1 and alphavbeta6 are involved in regulation of the immune system and epithelial homeostasis. They also indicate that alphavbeta6 functions as a tumor suppressor gene and that activation of TGFbeta by TSP-1 and alphavbeta6 contributes to normal tissue architecture and function.
Ludlow
Anna
A
The Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
Yee
Karen O
KO
Lipman
Ruth
R
Bronson
R
R
Weinreb
P
P
Huang
Xiaozhu
X
Sheppard
D
D
Lawler
J
J
D000505:Alopecia / Q000235:genetics; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D003433:Crosses, Genetic; D004848:Epithelium / Q000473:pathology; D005260:Female; D005831:Genital Diseases, Female / Q000235:genetics / Q000473:pathology; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D039641:Integrin beta Chains / Q000235:genetics*; D008136:Longevity / Q000235:genetics; D008171:Lung Diseases / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011014:Pneumonia / Q000235:genetics / Q000473:pathology; D013272:Stomach Diseases / Q000235:genetics / Q000473:pathology; D019700:Thrombospondin 1 / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D039641:Integrin beta Chains; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; C072170:integrin beta6