Changes in localization of human discs large (hDlg) during keratinocyte differentiation is associated with expression of alternatively spliced hDlg variants

Alternative spliced variants of the human discs large (hDlg) tumour suppressor are characterized by combinations of insertions. Here, using insertions 12- and 13-specific antibodies, we show that 12 and 13 variants have distinct distributions in epidermal and cervical epithelia. In skin and cervix, 13 variants are found in the cytoplasm. Cytoplasmic localization of 13 variants decreases as cervical keratinocytes differentiate, concomitant with relocalization to the cell periphery. 12 variants are found at the cell periphery of differentiated epidermal and cervical keratinocytes. Nuclear localization of 12 variants was evident in both tissues, with concentration of nuclear 12 variants in basal and parabasal cervical keratinocytes. A prominent nuclear localization of hDlg in cells of hyperproliferative layers of psoriatic lesions, but not in mature differentiated keratinocytes, together with 12 redistribution in differentiating keratinocytes, suggests that nuclear hDlg functions may be pertinent to growth of undifferentiated cells. Supporting our findings in squamous tissues, a decrease of nuclear hDlg and an increase of membrane-bound and cytoplasmic hDIg upon calcium-induced keratinocyte differentiation were not concomitant processes. Furthermore, we confirm that the exit of 12 variants from the nucleus is linked to stimulation of epithelial differentiation. The dynamic redistribution of hDIg also correlated with a marked increase in the expression of 13 variants while the level of 12 variants showed only a moderate decrease. Because changes in the intracellular distribution of hDIg splice variants, and in their expression levels, correlate with changes in differentiation state we hypothesize that the different hDIg isoforms play distinct roles at various stages of epithelial differentiation.