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Critical Reviews™ in Eukaryotic Gene Expression

Impact factor: 1.571

ISSN Print: 1045-4403
ISSN Online: 2162-6502

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukarGeneExpr.v22.i2.40
pages 117-129

Targeting the Regulatory Machinery of BIM for Cancer Therapy

Hisashi Harada
Department of Oral and Craniofacial Molecular Biology, Massey Cancer Center, Virginia Commonwealth University Health Sciences System, Richmond VA, 23298
Steven Grant
Department of Medicine, Division of Hematology/Oncology, Massey Cancer Center, Virginia Commonwealth University Health Sciences System, Richmond VA, 23298

ABSTRACT

BIM represents a BH3-only proapoptotic member of the BCL-2 family of apoptotic regulatory proteins. Recent evidence suggests that in addition to its involvement in normal homeostasis, BIM plays a critical role in tumor cell biology, including the regulation of tumorigenesis through activities as a tumor suppressor, tumor metastasis, and tumor cell survival. Consequently, BIM has become the focus of intense interest as a potential target for cancer chemotherapy. The control of BIM expression is complex, and involves multiple factors, including epigenetic events (i.e., promoter acetylation or methylation, miRNA), transcription factors, posttranscriptional regulation, and posttranslational modifications, most notably phosphorylation. Significantly, the expression of BIM by tumor cells has been shown to play an important role in determining the response of transformed cells to not only conventional cytotoxic agents, but also to a broad array of targeted agents that interrupt cell signaling and survival pathways. Furthermore, modifications in BIM expression may be exploited to improve the therapeutic activity and potentially the selectivity of such agents. It is likely that evolving insights into the factors that regulate BIM expression will ultimately lead to novel BIM-based therapeutic strategies in the future.