Kruppel Like Transcription Factors Proteins


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 Kruppel Like Transcription Factors Proteins Background

Specificity Protein /Kruppel-like Factor Superfamily

SP1 is one of the 25 currently identified members of the SP/Kriippel-like factor (KLF) family of transcription factors. Members of this family are characterized by an amino-terminally located transcriptional regulatory domain, a variably located nuclear localization signal (NLS), and a carboxyl-terminally located DBD. SP family members also contain a buttonhead (BTD) box, CXCPXC, positioned near the amino-terminal end of the zinc fingers, and a SP box located close to the amino-terminal end of the protein, that are not present among identified KLF proteins.

The DBD, which contains three C2H2 zinc finger motifs of 25-30 amino acid residues in length, shares about 65%-97% homology among family members. The SP/KLF finger domain wraps around the major grove of the DNA, primarily interacting with a nucleotide triplet, comprised mostly of guanine-rich sequences. DBD of SP/KLF family members recognizes either or both of the highly similar core sequences, CGCCC (GC-box) and CACCC with different affinities. SP1, SP3, and SP4 bind with higher affinity to GC-boxes than to CACCC-boxes, whereas many of the KLFs bind preferentially to CACCC-boxes over GCboxes. Intriguingly, some SP/KLF members also recognize the basic transcription element (BTE) sequence of the rat cytochrome P450, family 1, subfamily A, polypeptide 1 (5'- gatcGAGAAGGAGGCGTGGCCAACgatc-3’), which distantly resembles the GC-box and CACCC core sequence.

SP/KLF factors can potentially compete in binding to GC-boxes, CACCC-boxes, and BTE, and affect each other’s transcriptional regulation when multiple members are expressed. However, it is not clear under what cellular context this competition results in repression or compensation in gene function. SP/KLF members contain NLS, which underlies their nuclear accumulation. Some SP/KLF members have NLS located within the zinc-finger domain, while others have NLS localized immediately upstream of this region. The significance of the difference in NLS location remains unknown. In contrast to the DBD domain, the amino-terminally located transcriptional regulatory domain of SP/KLF members share very little homology. These domains for different family members can consist of glutamine-rich (SP proteins), acidic (KLF4, KLF6, KLF7, KLF9), proline-rich (KLF1-5, KLF10, KLF11), or serine-rich (KLF4, KLF6-8, and KLF 12) regions, resulting in the transcriptional specificity of family members.

A common a-helical repression motif (AA/VXXL) found in the transcriptional regulatory domain of some SP/KLF family members (KLF9, KLF10, KLF11, KLF13, KLF 16) interacts with the PAH2 domain of the corepressor protein mSin3, resulting in transcriptional repression activity through the mSin3A/histone deacetylase complex. Interestingly, some SP/KLF members, i.e. SP3, SP4, KLF3, KLF9, KLF4, and KLF5, can function as both an activator and repressor of gene transcription, depending on cell or promoter context. Indeed, both activating and repressive domains have been identified in SP3 and KLF4.

While promoter analysis of individual SP/KLF members remains to be conducted in detail, all currently characterized 5’ regulatory elements of genes encoding various SP/KLF family members contain SP/KLF binding sites, indicating that SP/KLF proteins can directly affect the expression of other family members. KLF4 and KLF5 can respectively regulate transcription of the KLF4 gene in a positive or negative manner. SP1, but not SP3, represses the SP4 promoter. Moreover, Klfl-KO mice have reduced expression of KLF3, while Klf9-KO mice have enhanced expression of Klfl3 transcripts, indicating the negative regulation of KIJ3 and Klfl3 transcription by Klfl and Klf9, respectively.