Genes encoding
growth-inhibitory proteins are postulated to be candidate
tumor suppressors. The identification of such
proteins may benefit the early diagnosis and
therapy of
tumors. Here we report the cloning and functional characterization of a novel human bone marrow stromal cell (BMSC)-derived
growth inhibitor (BDGI) by large scale random sequencing of a human BMSC cDNA library. Human BDGI
cDNA encodes a 477-amino
acid residue
protein that shares high homology with rat and mouse pregnancy-induced
growth inhibitors. The C-terminal of BDGI is identical to a novel human pregnancy-induced
growth inhibitor, OKL38. BDGI is also closely related to many other eukaryotic
proteins, which together form a novel and highly conserved family of BDGI-like
proteins. BDGI overexpression inhibits the proliferation, decreases anchorage-dependent growth, and reduces migration of MCF-7 human
breast cancer cells, whereas down-regulation of BDGI expression promotes the proliferation of MCF-7 and HeLa cervix epitheloid
carcinoma cells. Interestingly, the inhibitory effect of BDGI on MCF-7 cells is more potent than that of OKL38. We demonstrate that BDGI induces cell cycle arrest in S phase and subsequent apoptosis of MCF-7 cells, which is likely to account for the antiproliferative effects of BDGI. This process may involve up-regulation of p27Kip1 and down-regulation of
cyclin A, Bcl-2, and Bcl-xL. The inhibitory effect of BDGI on cell proliferation and the induction of apoptosis were also observed in A549
lung cancer cells but not HeLa cells. These results indicate that BDGI might be a
growth inhibitor for human
tumor cells, especially
breast cancer cells, possibly contributing to the development of new therapeutic strategies for
breast cancer.