From repression domains to designer zinc finger proteins: a novel strategy of intracellular immunization against HIV.
Tissue-specific gene regulation of eukaryotic organisms is to a large extent mediated by transcription factors that interact with genomic DNA sequences in a sequence-specific manner. The purpose of this synopsis is to put forward the potential of designer zinc finger proteins in treating infections of human immunodeficiency virus (HIV). Artificial transcription factors containing designer zinc finger structures fused to activator or repressor domains have been designated Transcription Response Modifiers (TRMs). The principle of engineering TRMs has been derived from the analysis of human Krüppel-type zinc finger genes and their products. Our research efforts encompass two fascinating features that are displayed by the human Krüppel-type zinc finger protein KOX1: 1) the Krüppel-type zinc finger domains display rules of sequence-specific DNA recognition, and 2) the evolutionarily conserved Krüppel-associated box (KRAB) presents one of the strongest transcriptional repressors identified so far in mammalian organisms. The KRAB repressor activity is postulated to be mediated through co-repressor molecules, such as Silencing Mediating Protein-1 (SMP-1). Thus, the structural organization and functional analysis of zinc finger proteins revealed principles of zinc finger transcription factors that are applicable for reducing the viral load in individuals infected with HIV. In this article, a novel concept of generating therapeutic proteins is outlined that might be conceptually promising in modulating gene expressions of any kind.
Thiesen
H J
HJ
Institut für Immunologie, Rostock, Germany.
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D015195:Drug Design; D006678:HIV / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D007114:Immunization / Q000379:methods*; D051741:Kruppel-Like Transcription Factors; D008954:Models, Biological; D008969:Molecular Sequence Data; D015202:Protein Engineering; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D012191:Retroviridae Proteins / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014779:Virus Replication; D016335:Zinc Fingers / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D012191:Retroviridae Proteins; D014157:Transcription Factors; D004247:DNA