Differences in MHC and TAP-1 expression in cervical cancer lymph node metastases as compared with the primary tumours

Cromme, F. V.; Bommel, Peter F. J. Van; Walboomers, J. M. M.; Gallee, M.P.W.; Stern, Peter L.; Kenemans, P.; Helmerhorst, Th.J.M.; Stukart, M. J.; Meijer, C. J. L. M.

doi:10.1038/bjc.1994.231

Cited by 130 publications

(87 citation statements)

References 40 publications

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“…Some of these genes, such as those encoding class I heavy chains, ␤ 2 m, and TAP1, are partially suppressed, whereas transcripts encoded by TAP2, LMP2, and LMP7 genes are undetectable, as are the corresponding protein products. In other tumors, other combinations of these genes are down-regulated (24,29,46,47).…”

Section: Discussionmentioning

confidence: 99%

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Arons

Kunin

Schechter

et al. 2001

The Journal of Immunology

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In accordance with the key role of MHC class I molecules in the adaptive immune response against viruses, they are expressed by most cells, and their expression can be enhanced by cytokines. The assembly and cell surface expression of class I complexes depend on a continuous peptide supply. The peptides are generated mainly by the proteasome and are transported to the endoplasmic reticulum by a peptide transport pump consisting of two subunits, TAP1 and TAP2. The proteasome low molecular weight polypeptide (2 and 7), as well as TAP (1 and 2) genes, are coordinately regulated and are induced by IFNs. Despite this coordinate regulation, examination of tumors shows that these genes can be discordantly down-regulated. In pursuing a molecular explanation for these observations, we have characterized the mouse TAP2 promoter region and 5′-flanking sequence. We show that the 5′ untranslated regions of TAP2 genes have a characteristic genomic organization that is conserved in both the mouse and the human. The mouse TAP2 promoter belongs to a class of promoters that lack TATA boxes but contain a MED1 (multiple start site element downstream) sequence. Accordingly, transcription is initiated from multiple sites within a 100-nucleotide window. An IFN regulatory factor 1 (IRF1)/IRF2 binding site is located in this region and is involved in both basal and IRF1-induced TAP2 promoter activity. The implication of the extensive differences found among the promoters of class I heavy chain, low molecular weight polypeptide, and TAP genes, all encoding proteins involved in Ag presentation, is discussed.

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Section: Discussionmentioning

confidence: 99%

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Arons

Kunin

Schechter

et al. 2001

The Journal of Immunology

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“…Loss of MHC class I molecules is a frequent event in both premalignant and malignant cervical lesions (Connor and Stern, 1990;Cromme et al, 1993a,b) and loss of the peptide transporter subunit TAP1 has also been found in malignant and metastatic lesions (Cromme et al, 1994b;Keating et al, 1995). It appears that there is no clear correlation between the presence of HPV DNA, or HPV 16 E7 transcripts and the MHC phenotype in cervical lesions (Bartholomew et al, 1995;Cromme et al, 1993b).…”

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confidence: 99%

“…Complete or heterogeneous loss of class I molecules associated with loss of TAP1 expression has been demonstrated (Cromme et al, 1994a;Keating et al, 1995), whereas a signi®cant increase in class I downregulation, accompanied by loss of TAP1 expression, was observed in metastatic cells in comparison to primary tumours (Cromme et al, 1994b). Transcriptional repression of other major components of the antigen presentation pathway by Ad 12 has been reported.…”

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confidence: 99%

Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins

2000

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We have examined the possibility that the E7 proteins of the high-risk human papillomavirus (HPV) type 16 and 18 and the oncogenic adenovirus (Ad) type 12 E1A protein share the ability to down-regulate the expression of components of the antigen processing and presentation pathway, as a common strategy in the evasion of immune surveillance during the induction of cell transformation. Expression of the HPV 18 E7 oncoprotein, like Ad 12 E1A, resulted in repression of the major histocompatibility complex (MHC) class I heavy chain promoter, as well as repression of a bidirectional promoter that regulates expression of the genes encoding the transporter associated with antigen processing subunit 1 (TAP1) and a proteasome subunit, low molecular weight protein 2 (LMP2). HPV 16 E7 also caused a reduction in class I heavy chain promoter activity, however it did not have any signi®cant e ect on the activity of the bidirectional promoter. Interestingly, expression of the low-risk HPV 6b E7 protein resulted in an increase in MHC class I heavy chain promoter activity, while repressing the TAP1/LMP2 promoter. Interference with the class I pathway could also explain the ability of low-risk HPVs in inducing benign lesions. Oncogene (2000) 19, 4930 ± 4935.

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“…It should be remembered that in about 70% of CC the production of MHC class I molecules is downregulated and these patients have a worse prognosis (Connor et al, 1993;Keating et al, 1995). It has also been reported that MHC class I expression in metastases is lower than in primary tumours (Cromme et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Metastatic MHC class I-negative mouse cells derived by transformation with human papillomavirus type 16

et al. 2001

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In the endeavour to develop a model for studying gene therapy of cancers associated with human papillomaviruses (HPVs), mouse cells were transformed with the HPV type 16 (HPV16) and activated H-ras oncogenes. This was done by contransfection of plasmid p16HHMo, carrying the HPV16 E6/E7 oncogenes, and plasmid pEJ6.6, carrying the gene coding for human H-ras oncoprotein activated by G12V mutation, into secondary C57BL/6 mouse kidney cells. An oncogenic cell line, designated MK16/1/IIIABC, was derived. The epithelial origin of the cells was confirmed by their expression of cytokeratins. No MHC class I and class II molecules were detected on the surface of MK16/1/IIIABC cells. Spontaneous metastases were observed in lymphatic nodes and lungs after prolonged growth of MK16/1/IIIABC-induced subcutaneous tumours. Lethally irradiated MK16/1/IIIABC cells induced protection against challenge with 10 5 homologous cells, but not against a higher cell dose (5 × 10 5 ). Plasmids p16HHMo and pEJ6.6 were also used for preventive immunization of mice. In comparison with a control group injected with pBR322, they exhibited moderate protection, in terms of prolonged survival, against MK16/1/IIIABC challenge ( P < 0.03). These data suggest that MK16/1/IIIABC cells may serve as a model for studying immune reactions against HPV16-associated human tumours. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Differences in MHC and TAP-1 expression in cervical cancer lymph node metastases as compared with the primary tumours

Cited by 130 publications

References 40 publications

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins

Metastatic MHC class I-negative mouse cells derived by transformation with human papillomavirus type 16

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