The regulation of albumin and alpha-fetoprotein gene expression in mammals.

Albumin and alpha-fetoprotein (AFP) are two plasma proteins synthesized by the liver and the yolk sac. The production of these major proteins is subject to considerable and characteristic variations during both the course of development and hepatic carcinogenesis. It is therefore a system of choice for the analysis of genetic expression during normal differentiation and the cancerous state of eukaryotic cells. The knowledge of regulatory mechanisms at the cellular and molecular levels of the albumin and AFP genes has recently made great progress: 1) the cells which are responsible for the synthesis of albumin and AFP in the liver and other organs have been defined by conjointly using in vitro and in vivo molecular hybridization techniques; 2) the organization of these genes and their adjoining regions has been established in the rat, the mouse and man; 3) the level at which the synthesis of these two proteins is regulated has been determined; it is the transcriptional level. The transcriptional regulation of the albumin and AFP genes could be the result of genome and/or chromatin conformation level modifications. Different groups have shown that: 1) the global structure of the albumin and AFP genes does not change during the course of development and hepatic carcinogenesis; 2) modifications at the level of the methylation of certain specific cytosines could be associated with the variations in the transcription of these genes; 3) global or local (hypersensitive sites with DNase I) changes of chromatin conformation could be correlated to the potential or the overt activity of the transcription of these genes. Very recently certain 'regulatory' regions having cis 'enhancer' or 'silencer' properties have been detected upstream from the albumin and AFP genes. These regions are hypothesized to be DNA 'target' sequences on which trans-acting regulatory factors are fixed and which control the transcription of these genes. Starting from the framework of this recent work, a model of albumin and AFP gene regulation is proposed.