SummarySp1-like proteins and Krüppel-like factors (KLFs) are highly related zinc-finger proteins that are important components of the eukaryotic cellular transcriptional machinery. By regulating the expression of a large number of genes that have GC-rich promoters, Sp1-like/KLF transcription regulators may take part in virtually all facets of cellular function, including cell proliferation, apoptosis, differentiation, and neoplastic transformation. Individual members of the Sp1-like/KLF family can function as activators or repressors depending on which promoter they bind and the coregulators with which they interact. A long-standing research aim has been to define the mechanisms by which Sp1-like factors and KLFs regulate gene expression and cellular function in a cell-and promoter-specific manner. Most members of this family have been identified in mammals, with at least 21 Sp1-like/KLF proteins encoded in the human genome, and members are also found in frogs, worms and flies. Sp1-like/KLF proteins have highly conserved carboxyterminal zinc-finger domains that function in DNA binding. The amino terminus, containing the transcription activation domain, can vary significantly between family members. The electronic version of this article is the complete one and can be found online at

Recent studies using glycogen synthase kinase-3B (GSK-3B)-deficient mouse embryonic fibroblasts suggest that GSK-3B positively regulates nuclear factor KB (NFKB)-mediated gene transcription. Because NFKB is suggested to participate in cell proliferation and survival pathways in pancreatic cancer, we investigated the role of GSK-3B in regulating these cellular processes. Herein, we show that pancreatic cancer cells contain a pool of active GSK-3B and that pharmacologic inhibition of GSK-3 kinase activity using small molecule inhibitors or genetic depletion of GSK-3B by RNA interference leads to decreased cancer cell proliferation and survival. Mechanistically, we show that GSK-3B influences NFKBmediated gene transcription at a point distal to the IK kinase complex, as only ectopic expression of the NFKB subunits p65/p50, but not an IK kinase B constitutively active mutant, could rescue the decreased cellular proliferation and survival associated with GSK-3B inhibition. Taken together, our results simultaneously identify a previously unrecognized role for GSK-3B in cancer cell survival and proliferation and suggest GSK-3B as a potential therapeutic target in the treatment of pancreatic cancer. (Cancer Res 2005; 65(6): 2076-81)

SummaryThe largest family of zinc-finger transcription factors comprises those containing the Krüppel-associated box (or KRAB domain), which are present only in tetrapod vertebrates. Many genes encoding KRAB-containing proteins are arranged in clusters in the human genome, with one cluster close to chromosome 9q13 and others in centromeric and telomeric regions of other chromosomes, but other genes occur individually throughout the genome. The KRAB domain, which is found in the amino-terminal region of the proteins, behaves as a transcriptional repressor domain by binding to corepressor proteins, whereas the C 2 H 2 zinc-finger motifs bind DNA. The functions currently proposed for members of the KRAB-containing protein family include transcriptional repression of RNA polymerase I, II, and III promoters and binding and splicing of RNA. Members of the family are involved in maintenance of the nucleolus, cell differentiation, cell proliferation, apoptosis, and neoplastic transformation. Gene organization and evolutionary historyZinc-finger proteins containing the Krüppel-associated box (KRAB-containing proteins) were discovered in 1991 by Bellefroid et al. [1]. They make up approximately one third (290) of the 799 different zinc-finger proteins present in the human genome, and as a result, this group of proteins is the largest single family of transcriptional regulators in mammals. Many genes encoding KRAB-containing proteins are arranged in clusters, but others occur individually throughout the genome. The best characterized cluster is on 19q, containing 148 genes (51% of the family) within a region close to 19q13 [2]; other clusters are in centromeric and telomeric regions of other chromosomes. In particular, members of the family containing SCAN domains (see below) are clustered on 3p21-22, 6p21-22, 16p13.3, and 17p12-13. Non-clustered genes encoding KRAB-containing proteins are scattered over the other chromosomes, with about half on autosomes and half on sex chromosomes. Although the expression of genes of other clustered families, such as homeobox genes, is coregulated, it remains to be determined whether a comparable mechanism operates for genes encoding KRAB-containing proteins, and more studies are needed to show how chromosome organization influences the expression patterns of this family.As shown in Figure 1, KRAB-containing proteins are characterized by the presence of a DNA-binding domain made up of between 4 and over 30 zinc-finger motifs and a KRAB domain. The KRAB domain, located near the amino terminus of the protein, consists of one or both of the KRAB A box and the KRAB B box (see below). Other domains, such as the SCAN domain, are found in a small subset of members of the family [2,3] (Table 1). The two boxes of the KRAB domain are always encoded by individual exons separated by introns of variable sizes. This exon-intron composition allows the generation of different products by alternative splicing. In fact, zinc-finger proteins that contain only a KRAB A domain, for instance, can originate...