Oncogene database

330

BIRC3

baculoviral IAP repeat containing 3;BIRC3;baculoviral IAP repeat containing 3

IAP homolog C|IAP-1|RING finger protein 49|TNFR2-TRAF signaling complex protein|TNFR2-TRAF-signaling complex protein 1|apoptosis inhibitor 2|baculoviral IAP repeat-containing 3|baculoviral IAP repeat-containing protein 3|inhibitor of apoptosis protein 1|m

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.

Proper regulation of nuclear factor kappaB (NF-kappaB) transcriptional activity is required for normal lymphocyte function, and deregulated NF-kappaB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-kappaB-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappaB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-kappaB pathway in B lymphoproliferative disease.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a prototypical cancer that occurs in the setting of chronic inflammation and an important model for understanding how deregulated NF-kappaB transcriptional activity contributes to malignancy. Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics. However, in a subset of MALT lymphomas, chromosomal translocations are acquired that render the lymphoma antigen-independent. The recurrent translocation t(11;18)(q21;q21) is associated with failure to respond to antibiotic therapy and increased rate of dissemination. This translocation creates the API2-MALT1 fusion oncoprotein, which comprises the amino terminus of inhibitor of apoptosis 2 (API2 or cIAP2) fused to the carboxy terminus of MALT1. A common characteristic of chromosomal translocations in MALT lymphoma, including t(11;18), is that genes involved in the regulation of the NF-kappaB transcription factor are targeted by the translocations, and these genetic perturbations thereby result in deregulated, constitutive NF-kappaB stimulation. In the last decade, great insights into the roles of API2 and MALT1 in NF-kappaB signaling have been made. For example, recent pivotal studies have uncovered the long sought-after proteolytic activity of MALT1 and have demonstrated its critical involvement in the survival of certain lymphomas. Here, we review the current understanding of the role of MALT1 in normal lymphocyte function and lymphomagenesis. We then highlight our recent work that has revealed an intriguing link between the proteolytic activity of the API2-MALT1 fusion and its ability to influence lymphomagenesis by cleaving a key NF-kappaB regulatory protein, NF-kappaB-inducing kinase.