Trends in Biochemical Sciences
ReviewMammalian Krüppel-like transcription factors: more than just a pretty finger
Section snippets
The DNA-binding domain: a defining family feature
The key feature of the family is the presence of a DNA-binding domain consisting of three Krüppel-like zinc fingers. This type of finger is present in the Drosophila melanogaster developmental regulator Krüppel and has several distinguishing characteristics: zinc is chelated by means of two cysteine and two histidine residues (which have slightly variable spacings); and the fingers are connected by a characteristic Krüppel-link, in which the finger and link sequences are Phe/Tyr-X-Cys-X2–4-Cys-X
Differences within the family
Although all family members, by virtue of their related DNA-binding domains, bind to similar elements in vitro, they have distinct activities in vivo. These differences reflect at least two features that are not shared by family members: expression profile and the sequence of the activation/repression domain. The first members of the family to be identified, SP1 and the related proteins SP2–SP4 (Ref. 6), are broadly expressed – as are other more recently recognized proteins, such as ubiquitous
Missing family members: knockout analyses
Although expression studies provided useful information, the most dramatic demonstration of the biological roles of these proteins has come from gene-targeting experiments in mice. In addition to confirming general conclusions about the activities of several of the proteins, gene-targeting experiments have uncovered unforeseen and remarkably specific roles.
One of the first knockouts to be generated was the Eklf knockout (13, 14). Eklf is expressed at high levels in erythroid cells, and
Sibling rivalry
The fact that family members have conserved DNA-binding domains but share little homology elsewhere raises the possibility that they have distinct transcriptional activities – that is, some might be activators and others might be repressors. This has turned out to be the case. Whereas SP1, SP2 and SP4 generally function as strong activators of transcription, SP3 appears to be a potent repressor21. This story is somewhat complicated by the facts that SP3 exists as a mixture of three major
Contact with suitable partner proteins
Given that the family members all recognize similar DNA elements and, in many instances, are co-expressed in the same cell type, what determines which factor operates where and when? The most obvious possibility is that all the various factors present in a cell bind indiscriminately to target genes and contribute to expression to varying degrees, depending on their abundance. Recent evidence suggests that such lack of specificity is unlikely – in fact it appears that different factors are
Conclusion
For many years, genetic experiments in Drosophila have provided a guiding light for biologists working in complex mammalian systems. Definition of Krüppel-like fingers has allowed us to recognize Krüppel-like proteins as important regulatory factors. One of the difficulties with working in mammalian systems is that genes often exist as members of large families; the overlapping expression patterns and redundancy that can result can complicate interpretation of experiments. However, the
Acknowledgements
We thank members of our department for their reading of the manuscript and Gerd Blobel for his helpful comments. M. C. thanks the Australian NHMRC for support.
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