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Zheng, P, Guo, Y, Niu, Q, Levy, DE, Dyck, JA, Lu, S, Sheiman, LA and Liu, Y (1998) Proto-oncogene PML controls genes devoted to MHC class I antigen presentation. Nature 396:373-6
Fragments of foreign antigens associated with class I molecules of the major histocompatibility complex (MHC) are presented at the cell surface to elicit an immune response. This presentation requires the coordinated expression of several genes contained in the MHC, including those encoding the MHC class I heavy chain, the proteins LMP-2 and LMP-7, which are involved in the proteasomal degradation of cytosolic antigens into peptide fragments that are destined for association with MHC class I molecules, and TAP-1 and TAP-2, which transport these fragments across the membrane of the endoplasmic reticulum at the start of their journey to the cell surface. In many virus-transformed cell lines and spontaneous tumours, these genes are simultaneously repressed. However, the key factor(s) that are essential for their expression and repression have not been identified. Here we report that the proto-oncogene product PML induces expression of LMP-2, LMP-7, TAP-1 and TAP-2 in an MHC-class I-negative, recurrent tumour, leading to the re-expression of cell-surface MHC in tumours and to rejection of the tumours. PML also regulates MHC expression in untransformed fibroblasts. We conclude that malfunction of PML may enable a tumour to evade the immune defence of its host.
3T3 Cells; Amino Acid Sequence; Animals; Antigen Presentation; Cloning, Molecular; DNA, Complementary; Genes, Regulator; Histocompatibility Antigens Class I/immunology; Mice; Molecular Sequence Data; Mutation; Neoplasm Proteins/genetics; Nuclear Proteins; Protein Isoforms/genetics; Proto-Oncogenes; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors/genetics; Transcriptional Activation; Tumor Cells, Cultured; Tumor Suppressor Proteins
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