Disease relevance of Kr

• The product of the Drosophila segmentation gene Krüppel was produced in cultured insect cells using the baculovirus expression system [1].
• Our results show that Kr is required for neurons to differentiate into Bolwig organs, for fasciculation of the Bolwig nerve, and for this nerve to follow a specific pathway toward the synaptic targets in the larval brain [2].
• We have isolated six individual phages from a mouse genomic library on the basis of their DNA homology to Krüppel finger-coding probes, and describe here the DNA sequence and expression of two such clones containing finger-like structures [3].
• Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis [4].
• Previous characterization of GLI, a gene found to be amplified and expressed in a subset of human brain tumors, revealed the presence of five tandem zinc fingers related to those of Krüppel (Kr), a Drosophila segmentation gene of the gap class [5].

Psychiatry related information on Kr

• The predicted proteins probably control the expression of other genes and, by analogy with Kr and GLI, may be important in human development, tissue-specific differentiation, or neoplasia [5].

High impact information on Kr

• Hunchback is necessary and sufficient for first-born cell fates, whereas Krüppel is necessary and sufficient for second-born cell fates; this is observed in multiple lineages and is independent of the cell type involved [6].
• Gradients of Krüppel and knirps gene products direct pair-rule gene stripe patterning in the posterior region of the Drosophila embryo [7].
• Our data suggest that Kr provides cues for establishing the "central" pattern elements at the blastoderm stage, and that Kr activity is controlled by maternal effect genes acting at the poles [8].
• The formation of the Kr protein domain may involve ubiquitous activation of Kr gene expression which, however, is limited by region-specific repression through the action of the maternal anterior and posterior pattern organizer genes [8].
• In addition, the formation of the Kr protein domain depends on the activity of gap genes acting adjacent to the Kr domain, but it is independent of subordinate pair-rule gene activities [8].

Chemical compound and disease context of Kr

• Drosophila Krüppel gene product produced in a baculovirus expression system is a nuclear phosphoprotein that binds to DNA [1].

Biological context of Kr

• Using gene fusion analysis, we assayed for cis-acting sequences of the Kr gene which mediate transcriptional activation and localized gene expression in response to trans-acting factors [9].
• A 142 bp core fragment containing one low affinity hb and five medium to strong bcd protein binding sites drives gene expression in a Kr-like location in the centre of the embryo [9].
• To begin a mechanistic understanding of stripe formation, we locate binding sites for the Kr protein in both stripe enhancers [10].
• Competition for overlapping sites in the regulatory region of the Drosophila gene Krüppel [11].
• The Drosophila gap gene Krüppel (Kr) displays a complex spatiotemporal pattern of expression during embryogenesis [12].

Anatomical context of Kr

• The initial expression of the gap gene Krüppel (Kr) occurs in a precisely bounded central region of the Drosophila blastoderm embryo [9].
• We localize and describe regulatory elements within the 4.1-kilobase region proximal to the Kr promoter that are responsible for expression in the ectoderm, mesoderm, amnioserosa, and nervous system [12].
• We have studied the ability of the Drosophila gap proteins Krüppel and hunchback to function as transcriptional regulators in cultured cells [13].
• Krüppel (Kr) and snail (sna), two zinc finger repressors, are essential for segmentation and for the establishment of the mesoderm/neuroectoderm boundary, respectively [14].
• Characterization of the Krüppel protein extracted from infected cells showed that it is tightly bound to the nucleus, it binds to calf thymus DNA-cellulose, and it is phosphorylated [1].

Associations of Kr with chemical compounds

• Like repression domains identified in the Drosophila repressors Eve and Krüppel, the En repression domain is rich in alanine residues (26%), but unlike these other domains, is moderately charged (six arginine and three glutamic acid residues) [15].
• In particular, Kr protein selectively represses transcription mediated by the Sp1 glutamine-rich activation domain, tethered to the promoter by a GAL4 DNA-binding domain, but does not repress transcription stimulated by the acidic GAL4 activator [16].
• Disruption of a putative Cys-zinc interaction eliminates the biological activity of the Krüppel finger protein [17].
• Fusion between a novel Krüppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia [18].
• Furthermore, one point mutant with only a single glutamine on this surface altered to lysine abolished the ability of the Krüppel protein to repress, indicating the importance of the amino acid at residue 86 for repression [19].

Physical interactions of Kr

• We also demonstrate that the kni activator binds to the stripe 6 enhancer and present evidence for a competitive mechanism of Kr repression of stripe 6 [10].
• The products of the Drosophila gap genes hunchback and Krüppel bind to the hunchback promoters [20].
• The GAGA factor is the predominant sequence-specific DNA binding factor that interacts with the Kr promoter region, and the purified protein activates Kr transcription in vitro [21].

Enzymatic interactions of Kr

• The pathway of tissue specific gene regulation, apparently, branches beyond Krüppel to form at least a cut and a caudal branch [22].

Regulatory relationships of Kr

• Ectopic expression of the tll gene also represses segmentation by repressing the gap genes Krüppel and knirps and probably also pair rule genes [23].
• In contrast, Krüppel is a transcriptional repressor that can block transcription induced either by hunchback or by several different homeo box proteins [13].
• We identified cis-acting Kr control units which drive beta-galactosidase expression in 10 known locations of Kr expression in early and late embryos [24].

Other interactions of Kr

• Mutations in kni and Kr produce complex alterations in the Ubx expression pattern [25].
• We show that kni expression is repressed by tll activity, whereas it is directly enhanced by Kr activity [26].
• Forming the posterior border of the stripe involves a delicate balance between limiting amounts of the bcd activator and the Kr repressor [27].
• The anterior border of Kr, which lies 4-5 nucleus diameters posterior to nuclei that express gt mRNA, is set by a threshold repression mechanism involving very low levels of gt protein [28].
• Krüppel expression, on the other hand, was found to be rather similar to the Drosophila expression, both at early and late stages. eve expression starts with six stripes formed at blastoderm stage, while the seventh is only formed after the onset of gastrulation and germband extension [29].
• We identified Krüppel-binding proteins by mass spectrometry and found that SAP18 can both associate with Krüppel and support Krüppel-dependent repression [30].

Analytical, diagnostic and therapeutic context of Kr

• Based on Northern blot analysis, Kr function has been thought to be restricted to embryogenesis [31].
• The molecular cloning of the Krüppel locus will lead to an understanding of the crucial role that gap genes seem to have in early embryonic development [32].
• Southern blot analysis of "zoo" blots suggests that the Krüppel-associated box is highly conserved during evolution [33].
• We have identified early embryo proteins related to the segmentation gene Krüppel by [35S]methionine pulse labelling and two-dimensional gel electrophoresis [34].
• Sequence analysis shows that all of these clones encode peptides which share the consensus DNA-binding motif with the Drosophila zinc finger transcription factor krüppel [35].

References