Zhx2 and Zbtb20: novel regulators of postnatal alpha-fetoprotein repression and their potential role in gene reactivation during liver cancer

Abstract

The mouse alpha-fetoprotein (AFP) gene is abundantly expressed in the fetal liver, normally silent in the adult liver but is frequently reactivated in hepatocellular carcinoma. The basis for AFP expression in the fetal liver has been studied extensively. However, the basis for AFP reactivation during hepatocarcinogenesis is not well understood. Two novel factors that control postnatal AFP repression, Zhx2 and Zbtb20, were recently identified. Here, we review the transcription factors that regulate AFP in the fetal liver, as well as Zhx2 and Zbtb20, and raise the possibility that the loss of these postnatal repressors may be involved in AFP reactivation in liver cancer.

Figure 1

Alignment of the mouse and human AFP promoters and locations of major transcription factor binding sites. The upper rows represent the mouse sequence, the lower rows represent human sequence; vertical lines indicate conserved nucleotides. The arrows represent the sites of transcription initiation (designated +1), nucleotides in italics correspond to the 5’ end of exon 1. Locations of factor binding sites are shown. While most of these sites are conserved between mouse and human, the C/EBP sites, distal Nkx2.8 site (−176 to −170), as well as the 3’ end of the NFI site, are less conserved.

Figure 2

Diagram of the 836 amino acid Zhx2 (top) and 733 amino acid Zbtb20 (bottom) mouse proteins showing predicted motifs. The cross-hatched regions indicate the C2H2 zinc fingers, stippled regions in Zhx2 indicate homeodomains, and dark grey region in Zbtb20 indicates the BTB (Broad complex, tramtrack, bric-a-brac) domain.