Jer-Tsong Hsieh, Jose A. Karam, Wang Min an important role in modulating DAB2IP expression during prostate cancer progression. The regulation of the function of DAB2IP may not be confined to epigenetic modifications, as indicated by a recent report (17) of a patient with acute myeloid leukemia, in whom intron 9 of the MLL gene was translocated to exon 2 of the DAB2IP gene, thereby disrupting the DAB2IP pleckstrin homology domain. The observation of epigenetic or genetic instability raises the possibility that the rs1571801 polymorphism may cause the DAB2IP gene to be more susceptible to genetic alteration or epigenetic regulation in prostate cancer. Expression of Ras protein has also been assessed in primary and metastatic prostate cancer tumors. Most tumors expressed higher levels of Ras protein than normal prostate tissues (18), and increased cH-Ras mRNA expression in prostate cancer is associated with the progression of prostate cancer to androgen independence (19). Perhaps surprisingly, prostate cancer specimens from American men have an extremely low rate of mutation in the Ras gene (20). This implies that other effectors may be involved in increasing RAS protein levels in prostate cancer. DAB2IP appears to be a good candidate because it contains an amino acid sequence that is homologous to the GTPase-activating protein (GAP) domain of other RasGAPs that is functionally active based on biochemical and molecular biologic studies (8). In addition to the GAP domain and the pleckstrin homology domain (amino acids 20–70), which has a high affinity for certain phosphoinositides, DAB2IP contains several other functional motifs, such as a C2 domain (amino acids 90–120) involved in binding phospholipids in a calcium-dependent or-independent manner, a proline-rich domain (amino acids 796–805) involved in interacting with proteins that contain a SH3 domain, and a leucine zipper (amino acids 842–861), which mediates dimerization. The C2 domain of DAB2IP can also bind and activate apoptosis-stimulated kinase (ASK1), which is involved in the TNF-α–mediated apoptosis. In addition to the interaction of C2 domain with ASK1, DAB2IP mutants defective in GAP activity failed to increase ASK1 activity, suggesting that the GAP activity of DAB2IP is required for TNF-α–elicited ASK1 activity (21). Also, the GAP activity of DAB2IP is known to be a negative regulator for Ras-Raf-ERK