Krüppel-like Factors Regulate the Lama1 Gene Encoding the Laminin α1 Chain

Abstract

Laminin-1 (␣1␤1␥1), a basement membrane (BM) constituent, has been associated with differentiation processes and also with malignant progression. In the intestinal tissue, the ␣1 chain is expressed and secreted in the subepithelial BM during the developmental period; in the adult rodent tissue, it is restricted to the BM of the dividing cells. To understand how laminin ␣1 chain expression is regulated, we cloned and characterized a 2-kb promoter region of the Lama1 mouse gene. Analysis of the promoter was conducted in the Caco2-TC7 intestinal epithelial cells by transient transfection of serially deleted and site-directed mutated promoter constructs, by electrophoretic mobility shift assays, and expression of selected transcription factors. We determined that a proximal region, which includes an Sp1-binding GC box and a Krü ppel-like element, was important for the promoter activity. This region is conserved between the human and mouse genes. Interestingly, two Krü ppellike factors KLF4 and KLF5 exhibit opposing effects on the Lama1 promoter activity that are decreased and increased, respectively, in the intestinal epithelial cells. These data corroborate the complementary expression of KLF4 and KLF5 along the intestinal crypt-villus axis and the parallel expression of KLF5 and laminin ␣1 chain in the crypt region. Finally, we showed that glucocorticoids stimulate the promoter activity. This study is the first characterization of the Lama1 promoter; we identified regulatory elements that may account for the expression pattern of the endogenous protein in the mouse intestine.

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

“…A potential reason for this competing effect is due to physical competition of the two proteins in binding to a cognate sequence in the KLF4 promoter [13]. A similar competing effect between KLF4 and KLF5 in the transcription of several other genes has also been described, including those encoding smooth muscle α-actin [14] and laminin-1 [15].…”

Sonic hedgehog-dependent synthesis of laminin α1 controls basement membrane assembly in the myotome

“…Alternatively, it is possible that the same enhancer controls both sites of expression, because we showed that the pre-somitic mesoderm is not competent to respond to Shh signalling owing to the absence of Gli proteins (Borycki et al, 2000;McDermott et al, 2005). Two studies have unveiled a putative promoter or enhancer region upstream of exon 1 of Lama1 (Niimi et al, 2003;Piccinni et al, 2004). Further work is required to establish whether Shh-Gli signalling affects this transcriptional activity directly.…”

KLF4, p21 and context-dependent opposing forces in cancer

“…Although at least some of the functions of KLF4 and KLF6 seem to be similar, KLF5 has been proposed to have complementary functions to those of KLF4 (REF. 14), in that they have opposing effects on the expression of their shared target genes [64][65][66] . It is not entirely clear whether the settings in which KLF4 functions as an oncogene are similar to those in which KLF5 functions as a tumour suppressor, or vice versa.…”