Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3)

Abstract

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-kappa 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 alpha) 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.

Cyclin D1: polymorphism, aberrant splicing and cancer risk

“…Specifically, cyclin D1 has been shown to regulate a number of sequence-specific transcription factors, including C/EBPb (Lamb et al, 2003), STAT3 (Bienvenu et al, 2001), DMP1 (Inoue and Sherr, 1998), and BETA2/NeuroD (Ratineau et al, 2002). The largest class of transcription factors regulated by cyclin D1 belong to the nuclear receptor superfamily, and include the estrogen receptor (Zwijsen et al, 1998;Lamb et al, 2000), androgen receptor (Knudsen et al, 1999;Reutens et al, 2001;Petre et al, 2002;Burd et al, 2005), thyroid hormone receptor (Pibiri et al, 2001), and peroxisome proliferator activated receptor-g (Qin et al, 2003). In many cases cyclin D1 was shown to directly associate with the transcription factors, independent of CDK4 association, and modify transcription factor action through cell-cycle independent mechanisms.…”

Poly(cationic lipid)-mediated in vivo gene delivery to mouse liver

“…T 3 acts via its nuclear receptors which are ligand-dependent nuclear transcription factors, 24 causes an increase in cyclin D 1 mRNA and protein levels at an early phase of hepatocyte regeneration in rats, and in turn leads to transition of G 1 phase to the S phase of the cell cycle. 25 Thus, T 3 pretreatment may be considered as a potential non-invasive approach in the stimulation of hepatocyte proliferation for gene delivery experiments.…”

Mitogenesis by ligands of nuclear receptors: an attractive model for the study of the molecular mechanisms implicated in liver growth

“…13 The finding that many hepatomitogens are ligands of nuclear receptors of the same superfamily led us to postulate that: (a) ligands of nuclear receptors could represent a novel class of liver mitogens; and, (b) signal transduction pathways involved in nuclear receptormediated hepatocyte proliferation could be different from those involved in liver regeneration and mediated by classical membrane-receptors. 4,14 It is now known that early changes such as activation of transcription factors (AP-1, NF-kB and STAT3, C/EBP) and increased expression of immediate early genes (c-fos, c-jun, c-myc, LRF-1, egr-1) or growth factors (TGF-a, HGF) considered to be essential for liver regeneration after two-thirds PH, are not required in nuclear receptormediated hepatocyte proliferation. 14 Hepatocyte proliferation induced by ligands of nuclear receptors is also TNF-a and IL-6-independent.…”

“…The accelerated entry into S phase, following treatment with TCPOBOP, nafenopin (a member of PPs family) and T3, is correlated with a very rapid induction of cyclin D1, suggesting that activation of this cyclin by ligands of nuclear receptors is an early critical event, rather than the results of a series of gene activations, as seen in the PH model. 14 Thus, an unified concept is emerging regarding the possible mechanisms of hepatocyte proliferation induced by several ligands of the nuclear receptors. Further studies to characterize molecular interactions between cyclin D1 gene and TRs, PPARs, CAR and possibly other nuclear hormone receptors may be critical to verify the validity of this concept.…”