Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27

Abstract

Bis (Bag-3, CAIR), a Bcl-2-interacting protein, promotes the anti-apoptotic activity of Bcl-2 and increased levels of Bis have been observed in several disease models. The involvement of Bcl-2 and some Bcl-2-binding proteins in differentiation has recently been reported. However, the relevance of Bis to cellular differentiation remains unknown. The findings herein show that Bis expression is up-regulated during the differentiation of HL-60 cells. To investigate the effect of Bis expression on differentiation, we established Bis-overexpressing HL-60 cells (HL-60-bis). HL-60-bis cells have a low nuclear: cytoplasmic ratio and indented nucleus in WrightGiemsa staining, and an increased expression of CD11b in immunofluorescence study, indicating the promotion of differentiation. The overexpression of Bis also resulted in a retarded cell growth rate, accompanied by the accumulation of HL-60 cells at the G0/G1 phase of the cell cycle, which was sustained during the differentiation process. Western blot analysis revealed that the expression of p27, a representative inducer of cell cycle arrest at the G1 phase, was increased 2.5-fold in HL-60-bis cells compared to HL-60-neo cells. These results suggest that the Bis induced growth inhibition of HL-60 cells promotes G0/G1 phase arrest via up-regulation of p27, which seems to be a prerequisite for differentiation. Further studies will be required to define the exact roles of Bis on cellular differentiation more precisely.

IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

“…Indeed, it has previously been shown that BAG3 can physically associate with a number of proteins potentially involved in tumorigenesis (e.g., PLC-γ, Akt, Bcl-XL, HspB8) (12,13,43,44); however, no correlation between these interactions and the prosurvival effect of BAG3 has been provided. Similarly, although it has been clearly demonstrated that BAG3 can affect the levels and/or activity of a number of other proteins potentially involved in tumor transformation (e.g., p27, Rac1, the focal adhesion proteins FAK and paxillin, the matricellular signal regulator CCN1) (45)(46)(47)(48), neither a clear mechanism through which BAG3 regulates them nor a clear causative role of BAG3 antiapoptotic activity has been demonstrated. Clearly, we believe that some of these proteins may play a causative role in the mechanism of action of BAG3, together with the pathway elucidated in this paper, because it is likely that BAG3 interacts with and regulates a number of different proteins through its multiple protein-binding domains.…”

BAG-4/SODD and Associated Antiapoptotic Proteins Are Linked to Aggressiveness of Epithelial Ovarian Cancer

“…The pattern of Bcl-2 decreasing with increasing grade and Hsp70 increasing was present in endometrioid histology of ovarian cancers (D), but not in serous tumors. (26,43,44). Cytoplasmic BAG-3 is a chaperone for Bcl-2 and Hsp proteins; in the nucleus, however, the function of BAG-3 has not been elucidated.…”

Bis deficiency results in early lethality with metabolic deterioration and involution of spleen and thymus

“…Overexpression of Bis promotes the differentiation of human promyelocytic cells and cell cycle arrest (32). Roles for Bis in cell adhesion and migration have been recently reported by separate groups, although their results differ: in one study overexpression of Bis is shown to inhibit the migration and adhesion of breast cancer cell lines, whereas in the other study bis-deficient fibroblasts have reduced motility and delayed formation of focal adhesion complex (12,14).…”