The negative regulatory element (NRE) of human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR) is a defined region that has been reported to down- regulate LTR-directed HIV gene expression. However, information on the precise role of this region in regulating HIV gene transcription is lacking. We have investigated the possibility that these NRE sequences regulate HIV transcription by a mechanism mediated through a nuclear matrix-specific DNA-protein interaction. We find a nuclear matrix attachment region (MAR) present within the NRE of the HIV-1 LTR that recognizes a sequence-specific DNA-binding protein present in the nuclear matrix of HIV infected cells. Moreover, we also show that the purified DNA-binding nuclear matrix protein (NMP) specifically represses the DNA-binding activity of NF-kB. It is likely that the MAR and MAR-enriched specific DNA-binding NMP are brought into juxtaposition by the non- chromatin scaffolding of the nucleus, thus influencing NF-kB (and other nuclear proteins) DNA-binding activity through protein-protein and protein-DNA interactions. Our data suggest that one possible role of the NRE could be to act as a matrix attachment site in the nuclear matrix, thus, allowing interaction with a sequence- specific trans-acting factor. The negative effect on NF-kB activity due to this MAR-NMP-specific interaction provides a mechanism by which the NRE down-regulates HIV gene expression. The c-erbB-2 gene overexpression plays a major role in the pathogenesis of breast cancer. Binding studies detected a nuclear matrix protein (NMP) in human breast tumor tissues that recognizes a matrix-attachment region (MAR) in the immediate vicinity of the c-erbB-2 gene promoter. This NMP is expressed in breast tumor tissues and cell lines along with c-erbB-2, but is not found in corresponding normal tissues. Furthermore, when NMP purified from the breast tumors by its affinity to the MAR sequence is added to nuclear extracts of breast cancer cells, it selectively stimulates the binding of the NF-kB transcription factor to DNA. A model is suggested in which the association of the MAR-like sequence with the nuclear matrix raises the local concentration of the specific NMP, which in turn interacts with the nuclear factor NF-kB to increase its local level. Such a complex could explain at a molecular level the """"""""increase in NF-kB DNA-binding activity"""""""" often observed in c- erbB-2- and BRCA1-positive human breast tumors. The increased NF-kB activity could thereby contribute to breast cancer progression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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Large Bowel and Pancreatic Cancer Review Committee (LBP)
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National Cancer Institute Division of Basic Sciences
United States
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