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* Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy;
Department of Neurological Sciences, University of Verona, Italy; and
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
1Correspondence: Dipartimento di Tossicologia, Sezione di Oncologia e Patologia Molecolare, Via Porcell 4, 09124 Cagliari, Italy. E-mail: columbano{at}unica.it
The thyroid hormone (T3) affects cell growth, differentiation, and
regulates metabolic functions via its interaction with the thyroid
hormone nuclear receptors (TRs). The mechanism by which TRs mediate
cell growth is unknown. To investigate the mechanisms responsible for
the mitogenic effect of T3, we have determined changes in activation of
transcription factors, mRNA levels of immediate early genes, and levels
of proteins involved in the progression from G1 to S phase of the cell
cycle. We show that hepatocyte proliferation induced by a single
administration of T3 to Wistar rats occurred in the absence of
activation of AP-1, NF-
B, and STAT3 or changes in the mRNA levels of
the immediate early genes c-fos, c-jun, and c-myc. These
genes are considered to be essential for liver regeneration after
partial hepatectomy (PH). On the other hand, T3 treatment caused an
increase in cyclin D1 mRNA and protein levels that occurred much more
rapidly compared to liver regeneration after 2/3 PH. The early increase
in cyclin D1 expression was associated with accelerated onset of DNA
synthesis, as demonstrated by a 20-fold increase of
bromodeoxyuridine-positive hepatocytes at 12 h after T3 treatment
and by a 20-fold increase in mitotic activity at 18 h. An early
increase of cyclin D1 expression was also observed after treatment with
nafenopin, a ligand of a nuclear receptor (peroxisome
proliferator-activated receptor 
) of the same superfamily of
steroid/thyroid receptors. T3 treatment also resulted in increased
expression of cyclin E, E2F, and p107 and enhanced phosphorylation of
pRb, the ultimate substrate in the pathway leading to transition from
G1 to S phase. The results demonstrate that cyclin D1 induction is one
of the earlier events in hepatocyte proliferation induced by T3 and
suggest that this cyclin might be a common target responsible for the
mitogenic activity of ligands of nuclear receptors.—Pibiri, M.,
Ledda-Columbano, G. M., Cossu, C., Simbula, G., Menegazzi, M.,
Shinozuka, H., Columbano, A. Cyclin D1 is an early target in hepatocyte
proliferation induced by thyroid hormone (T3).
Key Words: nuclear receptor • cell cycle • liver
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