X-chromosome linked inhibitor of apoptosis, XIAP, is cellular caspase inhibitor and a key regulator of apoptosis. We and others have previously shown that XIAP expression is regulated primarily at the level of protein synthesis; the 5′ untranslated region (UTR) of XIAP mRNA contains an Internal Ribosome Entry Site (IRES) that supports cap-independent expression of XIAP protein during conditions of pathophysiological stress, such as serum deprivation or gamma irradiation. Here, we show that XIAP is encoded by two distinct mRNAs that differ in their 5′ UTRs. We further show that the dominant, shorter, 5′ UTR promotes a basal level of XIAP expression under normal growth conditions. In contrast, the less abundant longer 5′ UTR contains an IRES and supports cap-independent translation during stress. Our data suggest that the combination of alternate regulatory regions and distinct translational initiation modes is critical in maintaining XIAP levels in response to cellular stress and may represent a general mechanism of cellular adaptation.
A monoclonal antibody to carcinoembryonic antigen (CEA) (C46) was tested for its binding properties to colorectal cancer cells in vitro and for its localization in patients with primary colorectal cancer. Strong binding was found to disaggregated primary colorectal cancer cells, with a median of 66 per cent of the cells in the tumour gate binding the antibody. There was a median binding ratio of 8.6:1 compared with normal immunoglobulin. The pattern of immunohistological staining was typical of that for an antibody to CEA. All seven patients with primary colorectal cancer imaged pre-operatively using 111In-labelled C46 gave positive images. The median tumour:non-tumour antibody uptake ratio from resected specimens (n = 8) was 5.8:1. (1.7-7.6:1). Eight of 11 sites of secondary colorectal cancer gave positive images. The high affinity and good tumour localization of C46 have improved clinical imaging and increase the possibilities for targetting of antitumour agents.
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