Prostate apoptosis response gene-4 (par-4) abrogates the survival function of p185BCR-ABL in hematopoietic cells

Objective Prostate apoptosis response gene-4 (par-4) is deregulated in acute and chronic lymphatic leukemia. Given its pro-apoptotic role in neoplastic lymphocytes and evidence that par-4 antagonizes oncogenic Ras in solid tumors, we hypothesized that par-4 may act as a tumor suppressor impairing transformation induced by p185BCR-ABL. Materials and Methods The capacity of par-4 to interfere with factor independence induced by p185BCR-ABL and V12ras was evaluated by analysis of factor-independent growth of p185BCR-ABL/ par-4 and V12ras/par-4 tranduced cells. The expression of par-4 and p185BCR-ABL by the respective constructs was controlled by Western blot analysis. Activated Ras was detected by pull-down assay in the cell clones expressing p185BCR-ABL in the absence and presence of par-4. Results Expression of p185BCR-ABL causes factor independence, signifying a conversion toward a transformed phenotype in hematopoietic precursors. We demonstrate that par-4 completely abolishes factor independence induced by p185BCR-ABL and partially abrogates factor independence caused by activated V12ras. Evaluating the underlying molecular mechanisms, we show that par-4 hinders activation of oncogenic Ras and causes concomitant disruptions of p185BCR-ABL-mediated signaling. Conclusion We provide the first evidence that par-4 exhibits an antitransforming capacity by antagonizing p185BCR-ABL-induced factor-independent proliferation in hematopoietic cells.