The molecular signals controlling liver regeneration are becoming rapidly defined. Control of growth in regenerating liver has advanced from elusive serum factors and nutrient effects to identification of entirely new growth factors with apparent liver specificity as well as establishment of meaningful gene expression patterns for growth factors already known. Based on studies with hepatocyte cultures and gene expression in regenerating liver, the substances EGF, TGF alpha, HBGF-1 (aFGF), and two new substances (HPTA/HGF and Hepatopoietin B) have been defined as complete mitogens for hepatocytes and implicated in control of liver growth. The amino acid sequence of HPTA/HGF recently became clear and revealed interesting structural homologies in a molecule that might become the largest known growth factor. The plasticity of growth responses seen in liver may be controlled by these factors as well as by comitogenic substances such as norepinephrine which, although nonmitogenic per se, can initiate growth in ...

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.4.2.2404819

Liver regeneration: molecular mechanisms of growth control.

Significance of rare mRNA sequences in liver

The biochemistry of the regenerating liver

Cytoplasmic and polysomal polyadenylated mRNA [poly(A)+-mRNA] increased by 120% prior to the onset of DNA synthesis during the regeneration of rat liver following partial hepatectomy. Despite this large change in cytoplasmic mRNA and an approximately 50% increase in total nuclear RNA, the amount of polyadenylated nuclear RNA increased by only 15--20% during this time. Neither the average size of nuclear or of cytoplasmic polyadenylated mRNA nor the length of their poly(adenylic acid) [poly(A)] tracts changed during liver regeneration. Polysomal poly-(A)+-mRNA increased proportionately more and at a faster rate than rRNA during the first day following partial hepatectomy. Normal livers contained a substantial proportion of cytoplasmic poly(A)+-mRNA not associated with polysomes but this proportion was not altered in 3-h regenerating liver. Thus, in regenerating liver, most preexisting cytoplasmic mRNA does not appear to be recruited into polysomes prior to the substantial increase in the amount of cytoplasmic poly(A)+-mRNA.

Accumulation of polyadenylated mRNA during liver regeneration.

The application of nucleic acid hybridization techniques to the study of liver regeneration has led to a revision of some well-established ideas about the patterns of gene expression during regenerative growth. This paper focuses on two broad problems: a) the extent to which mRNA populations in regenerating liver differ qualitatively or quantitatively from those of normal liver, and b) the similarities and differences between the pattern of gene expression during liver regeneration and liver development. Answers to these questions have come from studies in normal and regenerating liver of, a) the proportion of non-repetitive and repetitive DNA transcribed, b) the complexity of mRNA populations and the abundance of sequences in these populations, c) the extent of homology between mRNA populations, d) the amounts of specific mRNAs for albumin, alphafetoprotein, and fibrinogen, and e) the transcription of some cellular oncogenes. Changes in the abundance of liver mRNA transcripts, without major qualitative alterations in the spectrum of sequences contained in the RNA populations, are sufficient to permit the transition of hepatocytes from a resting into a dividing state. Transcripts from at least two cellular oncogenes are included among the mRNA sequences which become more abundant during liver regeneration. Analysis of the expression of some specific genes (albumin, alphafetoprotein and fibrinogen) during liver regeneration suggests that there is little similarity between the patterns of gene expression in regenerating and developing liver.

Messenger RNA in regenerating liver: implications for the understanding of regulated growth.

Studies on poly(A) sequences associated with regenerating liver RNA

To determine whether massive gene activation occurs in rat liver following partial hepatectomy, DNA-RNA hybridization-saturation and RNA depletion experiments were performed. RNA was extracted from whole cells, nuclei, post-mitochondrial extracts, and polysomes obtained from livers of normal, sham-operated, and partially hepatectomized rats. The purified RNA was labeled with [3H]dimethyl sulfate in vitro and hybridized with nuclera DNA under conditions in which only repetitive sequence transcripts form hybrids with DNA. For comparative purposes, experiments were also performed with nuclear RNA labeled with [32P3phosphoric acid in vivo. The following observations were made: (a) for whole-cell RNA the saturation levels obtained in the hybrization reaction are the same regardless of the source of RNA USED (NORMAL, SHAM-OPERATED, OR PARTIALLY HEPATECTOMIZED RATS); (B) NO DIFFERENCES IN THE SATURATION LEVELS WERE FOUND WHEN LIVER NUCLEAR RNA from these three groups of animals were used; (c) the concentration of nuclear RNA from 6-hr regenerating liver necessary to saturate the DNA is slightly higher than that of nuclear RNA obtained from normal rat liver; (d) cytoplasmic RNA from 6-hr regenerating liver saturates the DNA at a much lower concentration than that required for RNA from normal or sham-operated rats. Our results suggest that for repetitive sequence transcripts, massive "derepression" of the genome does not occur at the early stages of liver regeneration. The alterations detected reflect primarily changes in RNA concentrations rather than qualitative alterations in gene expression. Increased transport of repetitive sequence transcripts from nucleus to cytoplasm appears to take place in regenerating liver.

https://cancerres.aacrjournals.org/content/canres/37/1/118.full.pdf

Roland F. Greene

Papers

Studies on poly(A) sequences associated with regenerating liver RNA

Analysis of Gene Expression in Regenerating Rat Liver by Hybridization of Nuclear and Cytoplasmic RNA with DNA