Abstract
In primary embryonal fibroblasts from transgenic mice expressing H-2 genes and a miniature swine class I transgene (PD1), transformation with the highly oncogenic Ad12 results in a reduction in peptide transporter and proteasome-associated (LMP2 and LMP7) gene expression, and suppression in transport and cell surface expression of all class I antigens. The selective suppression in transport of H-2 (but not of PD1) molecules in cells reconstituted for the expression of peptide transporter and LMP genes implied that an additional factor(s) is involved in the assembly of class I complexes. Here we show that the beta2m, H-2Db, and H-2Kb genes are transcribed and translated in Ad12-transformed cells. However, unlike normal and E1Ad5-transformed cells, in which beta2m is either secreted unbound or bound to class I heavy chains, in Ad12-transformed cells significant amounts of beta2m are retained in the cell bound to the membrane, but free of class I heavy chains. This abnormal turnover of beta2m in the Ad12-transformed cells suggests the existence of a novel beta2m-binding molecule(s) that sequesters beta2m, and this process may provide a mechanism by which transformation with Ad12 may subvert class I complex formation.
Highlights
The biochemistry and cell biology of antigen processing and presentation by class I MHC molecules has been analyzed in detail in recent years [5, 6]
We have shown previously that, in primary embryonal fibroblasts from transgenic mice expressing both endogenous H-2 genes and a miniature swine class I transgene (PD1), transformation with the highly oncogenic Ad12 results in inhibition of the transport of newly synthesized class I molecules via the Golgi apparatus, a significant reduction in peptide transporter (TAP1 and TAP2) and in proteasome-associated (LMP2 and LMP7) gene expression, and in suppression of cell surface
These data, as well as the fact that in Ad12-transformed cells, H-2 molecules were not recognized by conformation-independent antibodies [33, 34], raised the possibility that either the synthesis of 2m in these cells is defective and the class I heavy chains compete for a limited amount of 2m molecules (PD1 being more competitive), or that Ad12-transformed cells are deficient in a factor(s) that facilitate the assembly of 2m with a particular set of class I heavy chains (H-2)
Summary
We have shown previously that, in primary embryonal fibroblasts from transgenic mice expressing both endogenous H-2 genes and a miniature swine class I transgene (PD1), transformation with the highly oncogenic Ad12 results in inhibition of the transport of newly synthesized class I molecules via the Golgi apparatus, a significant reduction in peptide transporter (TAP1 and TAP2) and in proteasome-associated (LMP2 and LMP7) gene expression, and in suppression of cell surface. The results show an abnormal turnover of 2m molecules and suggest the existence of a novel 2m-binding molecule(s) that acts to retain 2m in the transformed cells
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