krppel - like factors ( klfs ) are members of the zinc - finger family of transcription factors named after their similarity to the drosophila gap gene krppel .
klfs are characterised by a dna - binding motif containing three well - conserved c2h2 zinc - finger domains located in the carboxy terminal of the protein capable of binding gc - rich sequences , such as caccc elements present in the proximal promoters of many eukaryotic genes [ 2 - 7 ] .
the transcriptional regulatory domains located in the amino terminal of different klfs are variable , resulting in their ability to interact with co - activators and/or co - repressors , culminating in the activation or repression of a given promoter activity .
the presence of variable structural motifs outside of the dna - binding domain of the klf family members is reflected in their functional diversity .
characteristic features , nomenclature , evolution and functions of the human klfs are reviewed here .
the 81-amino acid dna - binding zinc - finger domain is highly conserved among the members of the klf family , with more than 65 per cent amino acid sequence identity among the family members .
the specific amino acids critical for dna binding are highly conserved , imparting an ability to different klfs that interact with similar cis - elements , such as gt boxes or gc - rich sequences like caccc .
the c2h2 zinc finger present in the klfs consists of two short beta strands followed by an alpha helix . in the classical c2h2 zinc - finger domain , two conserved cysteines and histidines
the pattern of amino acid arrangement in a classical zinc finger is as follows : # -x - c - x(1 - 5)-c - x3-#-x5-#-x2-h - x(3 - 6)-[h / c ] , where c , h and x correspond to cysteine , histidine and any amino acid , respectively , and numbers indicate the number of residues separating the flanking amino acids .
the amino acids that are important for the stable fold of the zinc finger are marked with the # symbol .
the amino acid occupying the final position can be either histidine or cysteine . the linker sequence in between the zinc - finger domains ( tge(r / k)p(y / f)x ) is also highly conserved in klf proteins .
klfs were initially named after the tissue in which they were detected or highly expressed , such as erythroid klf ( eklf or klf1 ) , lung klf ( lklf or klf2 ) , gut - enriched klf ( gklf / ezf or klf4),[12 - 15 ] and intestinal - enriched klf ( iklf or klf5 ; also called bteb2 ) .
a few other klfs were named after the elements they bound , such as the core promoter - binding protein ( cpbp / zf9 or klf6 ) , basic transcription element - binding protein ( bteb1 or klf9 ) , or by their physiological responses , such as transforming growth factor--inducible early genes 1 and 2 ( tieg1 and tieg2 or klf10 and klf11 , respectively ) . considering that the tissue expression of klfs , the range of their nucleotide recognition sequences and their ability to regulate diverse functions is much broader than initially understood , the use of numerical nomenclature based on the chronological order of discovery ( such as klf1 , klf2 , klf3 . . .
) is recommended by the human genome organization gene nomenclature committee ( hgnc ) to avoid misleading connotations providing partial descriptions of their expression and/or function .
a search of the hgnc website http://www.genenames.org/index.html for ' krppel - like factor ' on 26th january 2010 identified 17 klf genes in the human genome .
names , chromosomal locations , sequence accession ids , previous symbols and aliases , if any , for these klfs are given in table 1 .
several other related proteins , such as the members of the sp family of proteins , gli2 , gli3 , and the pseudogene klf7p , are not included in this list , for the sake of brevity .
names , chromosomal locations , number of exons , sequence accession ids , previous symbols and aliases , if any , for different klfs .
klfs are closely related to the sp family of zinc - finger transcription factors , of which there are nine members in the human genome ( sp1-sp9 ) . currently , there are 17 klfs annotated in the human genome .
the high level of conservation of structure and function of klf proteins in different species is a reflection of their ancient evolutionary history .
the 17 genes encoding different klfs are scattered all over the human genome , and there are also 17 klf genes in the mouse genome .
this indicates that these genes are ancient and suggests the involvement of gene duplications and translocations in their evolution .
for example , while klf12 has eight exons , klf14 is encoded on a single exon ( table 1 ) . based on an extensive phylogenetic analysis with the amino acid sequences of klf proteins from different species
, it was proposed that the mammalian klf genes have evolved in two phases - the first in the chordate lineage , during the early emergence of vertebrates , and the second in the mammalian lineage .
this phylogenetic analysis also identified six different ascidian zinc - finger proteins as the ancestral genes for the distinct subgroups of vertebrate klf genes . in view of the intron - less nature of klf14 and its homology with klf16
phylogenetic analysis of the 17 human klf complete amino acid sequences by the neighbour - joining method using the clustalw2 program http://www.ebi.ac.uk/tools/es/cgi-bin/clustalw2 indicated that klfs 5 , 17 and 8 are related more to each other than to the rest of the klfs , which are further grouped into two major clades ( figure 1 ) . according to this analysis , klfs 9 and 16 are the most recent klfs to have diverged from each other , followed by klfs 6 and 7 ( figure 1 ) .
this is consistent with the similar expression pattern , common ability to interact with msin3a ( a core component of a large multiprotein co - repressor complex with associated histone deacetylase enzymatic activity ) and shared cellular function of cell cycle regulation attributed to klfs 9 and 16 ( table 2 ) .
phylogenetic tree generated using the complete amino acid sequence of human klf proteins by clustalw2 web - based program http://www.ebi.ac.uk/tools/es/cgi-bin/clustalw2 .
expression pattern , interacting co - factors , effect on gene expression and known functions of different klfs .
by virtue of their ability to activate and/or repress the expression of a large number of genes , klfs regulate a diverse array of developmental events and cellular processes such as haematopoiesis , cardiac remodelling , adipogenesis,[27,31,46,78 - 82 ] maintenance of stem cells,[83 - 86 ] epithelial barrier formation,[87 - 90 ] control of cell proliferation and neoplasia,[91 - 93 ] flow - mediated endothelial gene expression , skeletal and smooth muscle development , gluconeogenesis , monocyte activation , intestinal and conjunctival goblet cell development , ocular surface integrity , retinal neuronal regeneration   and neonatal lung development   ( table 2 ) .
this functional diversity of klfs is consistent with the variable amino terminal regulatory domains in different klfs that allow interaction with a diverse array of co - factors .
for example , klfs 3 , 8 and 12 interact with carboxy - terminal binding protein ( ctbp ) co - repressors through the pvdl(s / t ) repressor domain , while klfs 9 , 10 , 11 , 13 and 16 interact with histone deacetylases ( hdacs ) through a sin3 interaction domain ( sid ) , both resulting in transcriptional repression . klf4
interacts with co - activators such as p300 and cbp ( cyclic - amp - response - element - binding - protein - binding - protein ) to mediate transcriptional activation .
the functional diversity of klfs results in interesting conflicts , wherein different klfs have antagonistic effect(s ) on individual cellular processes .
similarly , adipogenesis is supported by klfs 4 , 5 and 15 , but is suppressed by klfs 2 and 3 .
a large body of work over the past 25 years has established the klfs as critical regulators of diverse functions in many parts of the body . in spite of this progress in our understanding of the properties of klfs ,
much remains to be uncovered . in order fully to understand the properties of klfs in diverse spatio - temporal contexts and physiological conditions , it is crucial to identify ( a ) the co - factors that they interact with ; ( b ) their target genes ; ( c ) the signal transduction pathways by which they are regulated ; and ( d ) their unique tissue - specific roles using conditional knockouts .
it is expected that these avenues of research will lead to exciting discoveries regarding the involvement of klfs in human health and disease .
i apologise to those colleagues whose work could not be cited owing to space constraints .
work in the author 's laboratory was supported by the nei career development award 1k22ey016875 - 01 , nei core grant for vision research ( 5p30 ey08098 - 19 ) , research to prevent blindness and the eye and ear foundation , pittsburgh , pa , usa .
 krppel - like factors ( klfs ) , members of the zinc - finger family of transcription factors capable of binding gc - rich sequences , have emerged as critical regulators of important functions all over the body . 
 they are characterised by a highly conserved c - terminal dna - binding motif containing three c2h2 zinc - finger domains , with variable n - terminal regulatory domains . currently , there are 17 klfs annotated in the human genome . in spite of their structural similarity to one another 
 , the genes encoding different klfs are scattered all over the genome . by virtue of their ability to activate and/or repress the expression of a large number of genes , klfs regulate a diverse array of developmental events and cellular processes , such as erythropoiesis , cardiac remodelling , adipogenesis , maintenance of stem cells , epithelial barrier formation , control of cell proliferation and neoplasia , flow - mediated endothelial gene expression , skeletal and smooth muscle development , gluconeogenesis , monocyte activation , intestinal and conjunctival goblet cell development , retinal neuronal regeneration and neonatal lung development . 
 characteristic features , nomenclature , evolution and functional diversities of the human klfs are reviewed here . 
Introduction
Characteristic features of the zinc-finger domain in KLFs
Nomenclature of KLFs
Evolution of KLFs
Functions of KLFs
Future directions
Acknowledgements