TGFBI Deficiency Predisposes Mice to Spontaneous Tumor Development

Abstract

Loss of TGFBI, a secreted protein induced by transforming growth factor-b, has been implicated in cell proliferation, tumor progression, and angiogenesis by in vitro studies. However, in vivo antitumor functions of TGFBI as well as the underlying molecular mechanism are not well understood. To these aims, we have generated a mouse model with disruption of TGFBI genomic locus. Mice lacking TGFBI show a retarded growth and are prone to spontaneous tumors and 7,12-dimethylbenz(a)anthracene-induced skin tumors. In relation to wild-type (WT) mouse embryonic fibroblasts (MEF), TGFBI À/À MEFs display increased frequencies of chromosomal aberration and micronuclei formation and exhibit an enhanced proliferation and early S-phase entry. Cyclin D1 is up-regulated in TGFBI À/À MEFs, which correlates with aberrant activation of transcription factor cyclic AMPresponsive element binding protein (CREB) identified by chromatin immunoprecipitation and luciferase reporter assays. TGFBI reconstitution in TGFBI À/À cells by either retroviral infection with WT TGFBI gene or supplement with recombinant mouse TGFBI protein in the culture medium leads to the suppression of CREB activation and cyclin D1 expression, and further inhibition of cell proliferation. Cyclin D1 up-regulation was also identified in most of the tumors arising from TGFBI À/À mice. Our studies provide the first evidence that TGFBI functions as a tumor suppressor in vivo.

Identification of PITX1 as a TERT Suppressor Gene Located on Human Chromosome 5

“…Thus, the physiological expression of PITX1, TGF␤I, and ELL2 mRNA negatively correlated with mtert mRNA expression in the B16F10 clones. TGF␤I encodes a secreted protein, transforming growth factor ␤ (TGF␤), that is known to be a regulator of telomerase activity through the repression of the hTERT gene (57). ELL2 encodes a member of the ELL family of RNA polymerase II elongation factors.…”

Matrix Metalloproteinase 9 (MMP-9)-dependent Processing of βig-h3 Protein Regulates Cell Migration, Invasion, and Adhesion

“…␤ig-h3 protein suppresses human breast tumor progression and malignant transformation of cells (27, 34 -38). Mutation or altered expression of ␤ig-h3 has been linked to the pathogenesis of human corneal dystrophy and osteogenesis (39). However, the underlying molecular mechanism of ␤ig-h3 effects is not well understood.…”

BIGH3: A Negative Regulator of Human Osteosarcoma Large Multicellular Spheroids

“…One possibility that we examined is that BIGH3 functions as a tumor suppressor that diminishes tumor viability by induction of apoptosis. In support of this possibility TGFBI −/− mice are predisposed to form tumors when compared to wild type mice [10]. Other investigators have shown that BIGH3 is downregulated in tumors and tumor cells of mesenchyme origin, indicating a tumor suppressor role [9] [58] [59] [60] [61] [62].…”

“…TGFBI −/− mice exhibited predisposition to develop various tumors, underscoring BIGH3's tumor suppressing property. Isolated TGFBI −/− mouse embryonic fibroblasts showed chromosomal abnormalities, increased cyclin D1 synthesis, and cell proliferation [10].…”