Oncogene database

329

BIRC2

baculoviral IAP repeat containing 2;BIRC2;baculoviral IAP repeat containing 2

IAP homolog B|IAP-2|NFR2-TRAF signalling complex protein|RING finger protein 48|TNFR2-TRAF-signaling complex protein 2|apoptosis inhibitor 1|baculoviral IAP repeat-containing 2|baculoviral IAP repeat-containing protein 2|inhibitor of apoptosis protein 2

11q22

protein-coding

Amplification of oncogenes is an important mechanism that can cause gene overexpression and contributes to tumor development. The identification of amplified regions might have both prognostic and therapeutic significance. We used primary lung carcinomas and lung cancer cell lines for restriction landmark genomic scanning (RLGS) to identify novel amplified sequences. Enhanced RLGS fragments that indicate gene amplification were observed in primary tumors and lung cancer cell lines of both non-small cell lung cancer and small cell lung cancer. We identified one novel amplicon on chromosome 11q22, in addition to previously reported amplicons that include oncogenes MYCC, MYCL1 and previously identified amplification of chromosomal regions 6q21 and 3q26-27. Amplification of 11q22 has been reported in other types of cancer and was refined to an approximately 1.19 Mbp region for which the complete sequence is available. Based on a patient sample with a small region of low-level amplification we were able to further narrow this region to 0.92 Mbp. Genes localized in this region include two inhibitors of apoptosis (cIAP1 and cIAP2). Immunohistochemistry and western blot analysis identified cIAP1 and cIAP2 as potential oncogenes in this region as both are overexpressed in multiple lung cancers with or without higher copy numbers.

BIRC2 and BIRC3 are closely related members of the inhibitor of apoptosis (IAP) family of proteins and play pivotal roles in regulation of nuclear factor-kappaB (NF-kappaB) signaling and apoptosis. Copy number loss for and somatic mutation of BIRC2 and BIRC3 have been frequently detected in lymphoid malignancies, with such genetic alterations being thought to contribute to carcinogenesis through activation of the noncanonical NF-kappaB signaling pathway. Here we show that BIRC2 and BIRC3 mutations are also present in a wide range of epithelial tumors and that most such nonsense or frameshift mutations confer direct transforming potential. This oncogenic function of BIRC2/3 mutants is largely independent of their ability to activate NF-kappaB signaling. Rather, ALL of the transforming mutants lack an intact RING finger domain, with loss of ubiquitin ligase activity being essential for transformation irrespective of NF-kappaB regulation. The serine-threonine kinase NIK was found to be an important, but not exclusive, mediator of BIRC2/3-driven carcinogenesis, although this function was independent of NF-kappaB activation. Our data thus suggest that, in addition to the BIRC2/3-NIK-NF-kappaB signaling pathway, BIRC2/3-NIK signaling targets effectors other than NF-kappaB and thereby contributes directly to carcinogenesis. Identification of these effectors may provide a basis for the development of targeted agents for the treatment of lymphoid malignancies and other cancers with BIRC2/3 alterations.