Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells

Abstract

Bone morphogenic protein (BMP)-4 inhibits proliferation and induces the apoptosis of myeloma cells. However, little is known about the molecular mechanisms of how BMP-4 executes this apoptosis. In this report, we investigated the roles of p53 and the endoplasmic reticulum (ER) in BMP-4-induced apoptosis of mouse hybridoma HS-72 cells. We found that 3 ng/ml of BMP-4 is sufficient to induce the expression of proapoptotic proteins, puma and bax, in a p53-dependent mechanism, and facilitate Ca 2 þ release from the ER to the cytosol, resulting in the activation of caspase-12 and ER dysfunction. Similarly to HS-72 cells, multiple myeloma cells with wild-type p53 genes show much higher sensitivity to BMP-4-induced apoptosis than cells without wild-type p53 genes, suggesting that wild-type p53 status is required for dysfunction of the ER during BMP-4-induced apoptosis in ER-enriched cells, such as hybridoma and myeloma cells. These findings demonstrate that the presence of wild-type p53 genes and enrichment of the ER determines the sensitivity to effective apoptosis by BMP-4, and suggest that ER stress-inducing agents would be valuable in the treatment of multiple myeloma.

Runx2-mediated activation of the Bax gene increases osteosarcoma cell sensitivity to apoptosis

“…This led to a marked decrease in Bcl2 to Bax ratio, a key determinant of cell sensitivity to apoptosis (Cory and Adams, 2002). These data are in agreement with findings recently reported by Fukuda et al (2006) showing that BMP4-induced upregulation of Bax in mouse hybridoma HS-72 cells leads to enhanced cell death through a p53-dependent mechanism. Our study was performed in a p53-null osteosarcoma cell line, Saos2, indicating the existence of a novel, p53-independent mechanism for Bax regulation by BMP2.…”

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis

“…There is mounting evidence showing that BMP4 treatment can induce p53-mediated apoptosis (Fukuda et al, 2006;Kim et al, 2006;Haubold et al, 2010). However, the molecular mechanisms connecting these two pathways are poorly understood.…”

“…Additionally, BMP4 is known to induce apoptosis in a p53 (TRP53)-dependent manner in cancer cells as well as oral epithelial cells (Fukuda et al, 2006;Kim et al, 2006;Haubold et al, 2010). p53 tumor suppressor is a transcription factor that induces cell growth arrest and apoptosis (Kerr et al, 1972).…”

A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer

“…Phosphorylation of the BMP-specific intracellular Smads (Smad-1, -5, and -8) allows them to bind the partnering co-Smad, Smad4 (Yamashita et al, 1995;Kawabata et al, 1998;Miyazono et al, 2000Miyazono et al, , 2001Moustakas et al, 2001;Chen et al, 2004). This complex of Smads and other DNA-binding proteins undergoes nuclear translocation and triggers transcriptional activation of target genes, including cell cycle regulators or apoptosis mediators such as p21/Cip1/Waf1, bax, and p53 (Chen et al, 2002;Pouliot and Labrie, 2002;Fukuda et al, 2006).…”