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HGNC Approved Gene Symbol: PSIP1
Cytogenetic location: 9p22.3 Genomic coordinates (GRCh38): 9:15,464,066-15,510,970 (from NCBI)
Transcriptional activation in human cell-free systems containing RNA polymerase II and general initiation factors requires the action of one or more additional coactivators. Ge et al. (1998) reported the isolation of cDNAs encoding 2 novel human transcriptional coactivators (p52 and p75) that are derived from alternatively spliced products of a single gene and share a region of 325 residues, but show distinct coactivator properties.
By immunoscreening a human lens epithelial cell cDNA library with antibodies from a cataract patient, Singh et al. (2000) isolated a cDNA encoding a protein that they named 'lens epithelium-derived growth factor' (LEDGF). They determined that LEDGF is identical to p75, a coactivator of both transcription and pre-mRNA splicing.
Singh et al. (2000) found that the LEDGF gene contains at least 15 exons and encodes LEDGF mRNA and p52 mRNA. Exons 1 through 15 encode LEDGF mRNA; exons 1 through 9 and part of intron 9 encode p52.
Ge et al. (1998) demonstrated strong interactions of both p52 and p75 with the VP16 activation domain and several components of the general transcriptional machinery. p52 is a potent broad-specificity coactivator, whereas p75 is less active for most activation domains.
Ge et al. (1998) found that p52 interacts not only with transcriptional activators and general transcription factors to enhance activated transcription, but also with the essential splicing factor ASF/SF2 both in vitro and in vivo to modulate ASF/SF2-mediated pre-mRNA splicing. Immunofluorescence studies indicated that the majority of endogenous p52 is colocalized with ASF/SF2 in the nucleoplasm of HeLa cells. These observations suggested that, in addition to functioning as a transcriptional coactivator, p52 may also act as an adaptor to coordinate pre-mRNA splicing and transcriptional activation of class II genes.
Singh et al. (2000) observed that in serum-free medium, LEDGF stimulated growth of lens epithelial cells, COS-7 cells, skin fibroblasts, and keratinocytes, and prolonged survival of these cell lines. Antibodies against LEDGF blocked cell growth and caused cell death. Singh et al. (2000) concluded that LEDGF, a regulatory factor, might play an important role in the growth and survival of a wide range of cell types.
Singh et al. (2000) found almost equal amounts of LEDGF/p75 and p52 expressed in lens epithelial cells in culture.
Nakamura et al. (2000) studied the effects of LEDGF on survival of embryonic chick retinal photoreceptor cells under serum starvation and heat stress. Immunohistochemistry detected LEDGF expression predominantly in the nucleus of neuroretinal cells, including photoreceptor cells. In the presence of LEDGF, photoreceptor cells showed increased resistance to serum starvation and heat stress and survived for longer periods. Levels of heat shock protein-90 (see 140571) were elevated in LEDGF-treated cells. Most retinal cells died in the absence of LEDGF. They authors concluded that LEDGF enhanced survival of retinal photoreceptor cells under serum starvation and heat stress.
Machida et al. (2001) found that LEDGF protected photoreceptor structure and function in both light-damaged and RCS rats (see 604705). However, LEDGF failed to rescue photoreceptors in a transgenic rat model of human retinitis pigmentosa (268000) carrying a P23H mutation in rhodopsin (180380.0001).
Ciuffi et al. (2005) noted that LEDGF binds both chromosomal DNA and human immunodeficiency virus (HIV) integrase, suggesting that it might direct HIV integration by a tethering interaction. They found that treatment of kidney and T-cell lines with short hairpin RNAs to achieve a strong knockdown of LEDGF resulted in a reduction of HIV integration in transcription units (i.e., genes) compared with control cells. Likewise, genes regulated by LEDGF were preferred integration sites. Knockdown of LEDGF also resulted in increased HIV integration in chromosomal regions with higher GC content, possibly due to LEDGF binding preferentially in AT-rich chromosomal regions. Ciuffi et al. (2005) proposed that LEDGF becomes enriched on genes by binding components of the transcriptional apparatus, thereby positioning itself to target HIV integration to these sites.
Llano et al. (2006) used intensified RNA interference and dominant-negative protein approaches to show that the cellular transcriptional coactivator lens epithelium-derived growth factor LEDGF/p75 is an essential HIV integration cofactor. The mechanism requires both linkages of a molecular tether that p75 forms between integrase and chromatin. Fractionally minute levels of endogenous p75 are sufficient to enable integration, showing that cellular factors that engage HIV after entry may elude identification in less intensive knockdowns.
Cherepanov et al. (2005) reported the crystal structure of the dimeric catalytic core domain of HIV-1 integrase complexed to the integrase-binding domain of LEDGF at 2-angstrom resolution. The structure elucidated the mode of recognition between the 2 proteins and revealed a potential target site on the integrase for the design of small molecule inhibitors to block the interaction.
By FISH, Singh et al. (2000) mapped the LEDGF gene to chromosome 9p22.2. They noted that the 9p22-p21 region is the site of chromosomal abnormalities in a variety of malignancies, including leukemia, glioma, lung cancer, and melanoma.
Cherepanov, P., Ambrosio, A. L. B., Rahman, S., Ellenberger, T., Engelman, A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Nat. Acad. Sci. 102: 17308-17313, 2005. [PubMed: 16260736] [Full Text: https://doi.org/10.1073/pnas.0506924102]
Ciuffi, A., Llano, M., Poeschla, E., Hoffmann, C., Leipzig, J., Shinn, P., Ecker, J. R., Bushman, F. A role for LEDGF/p75 in targeting HIV DNA integration. Nature Med. 11: 1287-1289, 2005. [PubMed: 16311605] [Full Text: https://doi.org/10.1038/nm1329]
Ge, H., Si, Y., Roeder, R. G. Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation. EMBO J. 17: 6723-6729, 1998. [PubMed: 9822615] [Full Text: https://doi.org/10.1093/emboj/17.22.6723]
Ge, H., Si, Y., Wolffe, A. P. A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2. Molec. Cell 2: 751-759, 1998. [PubMed: 9885563] [Full Text: https://doi.org/10.1016/s1097-2765(00)80290-7]
Llano, M., Saenz, D. T., Meehan, A., Wongthida, P., Peretz, M., Walker, W. H., Teo, W., Poeschla, E. M. An essential role for LEDGF/p75 in HIV integration. Science 314: 461-464, 2006. [PubMed: 16959972] [Full Text: https://doi.org/10.1126/science.1132319]
Machida, S., Chaudhry, P., Shinohara, T., Singh, D. P., Reddy, V. N., Chylack, L. T., Jr., Sieving, P. A., Bush, R. A. Lens epithelium-derived growth factor promotes photoreceptor survival in light-damaged and RCS rats. Invest. Ophthal. Vis. Sci. 42: 1087-1095, 2001. [PubMed: 11274090]
Nakamura, M., Singh, D. P., Kubo, E., Chylack, L. T., Jr., Shinohara, T. LEDGF: survival of embryonic chick retinal photoreceptor cells. Invest. Ophthal. Vis. Sci. 41: 1168-1175, 2000. [PubMed: 10752956]
Singh, D. P., Kimura, A., Chylack, L. T., Jr., Shinohara, T. Lens epithelium-derived growth factor (LEDGF/p75) and p52 are derived from a single gene by alternative splicing. Gene 242: 265-273, 2000. [PubMed: 10721720] [Full Text: https://doi.org/10.1016/s0378-1119(99)00506-5]
Singh, D. P., Ohguro, N., Kikuchi, T., Sueno, T., Reddy, V. N., Yuge, K., Chylack, L. T., Jr., Shinohara, T. Lens epithelium-derived growth factor: effects on growth and survival of lens epithelial cells, keratinocytes, and fibroblasts. Biochem. Biophys. Res. Commun. 267: 373-381, 2000. [PubMed: 10623627] [Full Text: https://doi.org/10.1006/bbrc.1999.1979]