DNA Binding Domains and Nuclear Localization Signal of LEDGF: Contribution of two Helix-Turn-Helix (HTH)-like Domains and a Stretch of 58 Amino Acids of the N-terminal to the Trans-activation Potential of LEDGF

Singh, D. P.; Kubo, Eri; Takamura, Yoshihiro; Shinohara, Toshimichi; Kumar, Anil; Chylack, Leo T.; Fatma, Nigar

doi:10.1016/j.jmb.2005.10.054

Cited by 60 publications

(93 citation statements)

References 56 publications

(97 reference statements)

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“…In the leukemia-related translocations, the COOH terminus of the LEDGF is fused to the NH 2 terminus of the nucleoprotein-98 gene. Such a fusion can result in the replacement of the NH 2 -terminal LEDGF sequences that act as transcriptional repressors with FXFG repeats of nucleoprotein-98 that possess strong transcriptional activation activity (45,49).…”

Section: Discussionmentioning

confidence: 99%

Lens Epithelium-Derived Growth Factor Is an Hsp70-2 Regulated Guardian of Lysosomal Stability in Human Cancer

et al. 2007

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Heat shock protein 70-2 (Hsp70-2) is a chaperone protein essential for the growth of spermatocytes and cancer cells. Here, we show that Hsp70-2 depletion triggers lysosomal membrane permeabilization and cathepsin-dependent cell death and identify lens epithelium-derived growth factor (LEDGF) as an Hsp70-2-regulated guardian of lysosomal stability in human cancer. Knockdown of LEDGF in cancer cells induces destabilization of lysosomal membranes followed by caspase-independent and Bcl-2-resistant cell death. Accordingly, ectopic LEDGF stabilizes lysosomes and protects cancer cells against cytotoxicity induced by anticancer agents that trigger the lysosomal cell death pathway. Remarkably, ectopic LEDGF also increases the tumorigenic potential of human cancer cells in immunodeficient mice, and LEDGF expression is increased in human breast and bladder carcinomas correlating with that of Hsp70-2 in invasive bladder cancer. Taken together, these data reveal LEDGF as an oncogenic protein that controls a caspase-independent lysosomal cell death pathway. [Cancer Res 2007;67(6):2559-67]

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Section: Discussionmentioning

confidence: 99%

Lens Epithelium-Derived Growth Factor Is an Hsp70-2 Regulated Guardian of Lysosomal Stability in Human Cancer

et al. 2007

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“…Consistent with this finding, the LEDGF gene is involved in chromosomal translocations in patients with various types of leukemia, resulting in a fusion with nucleoprotein-98 that retains the C terminus of LEDGF/p75 (90 -92). This domain has been implicated in DNA binding and transcription function (93), survival function (93,94), binding to human immunodeficiency virus integrase (95), and autoantibody recognition (96). It should be emphasized that anti-LEDGF/p75 antibodies are not specific for prostate cancer because they have been also detected, albeit at relatively low frequencies and titers, in "healthy individuals" and patients with various human inflammatory conditions (97).…”

Section: Cancer-associated Autoantibodies As Reporters Of Tumorigenesismentioning

confidence: 99%

Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer

Casiano

Mediavilla-Varela

Tan

2006

Molecular & Cellular Proteomics

121

106

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The recognition that human tumors stimulate the production of autoantibodies against autologous cellular proteins called tumor-associated antigens (TAAs) has opened the door to the possibility that autoantibodies could be exploited as serological tools for the early diagnosis and management of cancer. Cancer-associated autoantibodies are often driven by intracellular proteins that are mutated, modified, or aberrantly expressed in tumor cells and hence are regarded as immunological reporters that could help uncover molecular events underlying tumorigenesis. Emerging evidence suggests that each type of cancer might trigger unique autoantibody signatures that reflect the nature of the malignant process in the affected organ. The advent of novel genomic, proteomic, and high throughput approaches has accelerated interest in the serum autoantibody repertoire in human cancers for the discovery of candidate TAAs. The use of individual anti-TAA autoantibodies as diagnostic or prognostic tools has been tempered by their low frequency and heterogeneity in most human cancers. However, TAA arrays comprising several antigens significantly increase this frequency and hold great promise for the early detection of cancer, monitoring cancer progression, guiding individualized therapeutic interventions, and identification of novel therapeutic targets. Our recent studies suggest that the implementation of TAA arrays in screening programs for the diagnosis of prostate cancer and other cancers should be preceded by the optimization of their sensitivity and specificity through the careful selection of the most favorable combinations of TAAs.

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“…(A) LEDGF/p75 domain organization and previously described mutants used in the present study. Binding of recombinant protein to DNA in vitro is predominantly mediated by the NLS and dual copy of the AT-hook (ATh) DNA-binding motif, with the PWWP domain (gray shade) contributing a minor role (1,56,62). Chromatin binding is largely mediated by the PWWP domain and AT-hooks, with charged regions (CRs) 1 to 3 making secondary contributions (29,62).…”

mentioning

confidence: 99%

Identification and Characterization of PWWP Domain Residues Critical for LEDGF/p75 Chromatin Binding and Human Immunodeficiency Virus Type 1 Infectivity

Shun

Botbol

et al. 2008

J Virol

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Lens epithelium-derived growth factor (LEDGF)/p75 functions as a bimodal tether during lentiviral DNA integration: its C-terminal integrase-binding domain interacts with the viral preintegration complex, whereas the N-terminal PWWP domain can bind to cellular chromatin. The molecular basis for the integrase-LEDGF/ p75 interaction is understood, while the mechanism of chromatin binding is unknown. The PWWP domain is homologous to other protein interaction modules that together comprise the Tudor clan. Based on primary amino acid sequence and three-dimensional structural similarities, 24 residues of the LEDGF/p75 PWWP domain were mutagenized to garner essential details of its function during human immunodeficiency virus type 1 (HIV-1) infection. Mutating either Trp-21 or Ala-51, which line the inner wall of a hydrophobic cavity that is common to Tudor clan members, disrupts chromatin binding and virus infectivity. Consistent with a role for chromatin-associated LEDGF/p75 in stimulating integrase activity during infection, recombinant W21A protein is preferentially defective for enhancing integration into chromatinized target DNA in vitro. The A51P mutation corresponds to the S270P change in DNA methyltransferase 3B that causes human immunodeficiency, centromeric instability, and facial anomaly syndrome, revealing a critical role for this amino acid position in the chromatin binding functions of varied PWWP domains. Our results furthermore highlight the requirement for a conserved Glu in the hydrophobic core that mediates interactions between other Tudor clan members and their substrates. This initial systematic mutagenesis of a PWWP domain identifies amino acid residues critical for chromatin binding function and the consequences of their changes on HIV-1 integration and infection.Integration, catalyzed by the viral integrase protein, is an essential step in the replication cycles of all retroviruses. Integration into cellular chromatin provides an optimal environment for gene expression and ensures that the viral genetic material is inherited by daughter cells upon division. Integration proceeds via the following steps: (i) integrase binding to the cDNA end regions that are synthesized during reverse transcription; (ii) hydrolysis adjacent to invariant CA sequences near both 3Ј ends (3Ј processing); (iii) transfer of the reactive 3Ј-OH ends to the 5Ј-phosphates of a double-stranded cut in cellular chromatin (DNA strand transfer); and (iv) repair of the resulting DNA recombination intermediate, which is likely accomplished by host cell enzymes. (See reference 61 for a detailed overview of retroviral integration.)Although all retroviruses rely on integrase 3Ј processing and DNA strand transfer activities, significant differences exist in the way the various viral genera select their chromosomal integration sites. These differences manifest themselves at the level of local DNA sequence (20, 68) and genetic structure (reviewed in reference 2). Lentiviruses, for example, favor integration into active transcription uni...

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DNA Binding Domains and Nuclear Localization Signal of LEDGF: Contribution of two Helix-Turn-Helix (HTH)-like Domains and a Stretch of 58 Amino Acids of the N-terminal to the Trans-activation Potential of LEDGF

Cited by 60 publications

References 56 publications

Lens Epithelium-Derived Growth Factor Is an Hsp70-2 Regulated Guardian of Lysosomal Stability in Human Cancer

Lens Epithelium-Derived Growth Factor Is an Hsp70-2 Regulated Guardian of Lysosomal Stability in Human Cancer

Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer

Identification and Characterization of PWWP Domain Residues Critical for LEDGF/p75 Chromatin Binding and Human Immunodeficiency Virus Type 1 Infectivity

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