Related Experiment Video

Updated: Aug 10, 2026

Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1

Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1

Published on: February 25, 2016

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

M Pibiri¹, G M Ledda-Columbano, C Cossu

¹Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology

|April 9, 2001

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.

Insights

Thyroid hormone (T3) stimulates liver cell growth by rapidly increasing cyclin D1, a key cell cycle regulator. This mechanism differs from liver regeneration pathways and highlights cyclin D1 as a potential target for nuclear receptor ligands.

Area of Science:

Molecular Endocrinology
Cell Cycle Regulation
Hepatocyte Proliferation

Background:

Thyroid hormone (T3) influences cell growth and metabolism through thyroid hormone nuclear receptors (TRs).
The precise mechanisms by which TRs drive cell proliferation, particularly in hepatocytes, remain incompletely understood.
Previous studies suggest immediate early genes are crucial for liver regeneration, but their role in T3-induced proliferation is unclear.

Purpose of the Study:

To elucidate the molecular mechanisms underlying the mitogenic effects of thyroid hormone (T3) on hepatocytes.
To investigate the role of transcription factors, immediate early genes, and cell cycle proteins in T3-induced hepatocyte proliferation.
To compare the T3-mediated pathway with known liver regeneration mechanisms.

Main Methods:

Administration of T3 to Wistar rats to induce hepatocyte proliferation.
Analysis of transcription factor activation (AP-1, NF-kappa B, STAT3).
Quantification of immediate early gene mRNA levels (c-fos, c-jun, c-myc).
Measurement of cell cycle regulatory proteins (cyclin D1, cyclin E, E2F, p107) and pRb phosphorylation.
Assessment of DNA synthesis (bromodeoxyuridine incorporation) and mitotic activity.
Comparison with nafenopin treatment, a peroxisome proliferator-activated receptor alpha ligand.

Main Results:

T3-induced hepatocyte proliferation occurred independently of AP-1, NF-kappa B, STAT3 activation, and immediate early gene induction.
T3 rapidly increased cyclin D1 mRNA and protein levels, preceding DNA synthesis and mitotic activity.
T3 treatment also elevated cyclin E, E2F, p107 expression, and pRb phosphorylation, facilitating G1 to S phase transition.

Conclusions:

Cyclin D1 induction is an early and critical event in T3-mediated hepatocyte proliferation.
The T3-induced proliferation pathway differs significantly from that of liver regeneration post-partial hepatectomy.
Cyclin D1 may serve as a common downstream target for the mitogenic actions of various nuclear receptor ligands.

Read full analysis

More Related Videos

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

Related Concept Videos

Positive Regulator Molecules

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.

Positive Regulator Molecules

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.

Inhibition of Cdk Activity

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

M-Cdk Drives Transition Into Mitosis

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...

Inhibition of CDK Activity

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...

M-Cdk Drives Transition Into Mitosis

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...

Articles linked to this work by shared authors, journal, and citation graph.

Analysis of metabolomics profile in hypothyroid patients before and after thyroid hormone replacement.

Journal of endocrinological investigation·2020

Neuromuscular maturation in the neonate: Combined electroneurographic and ultrasonographic study.

Early human development·2019

Neurophysiological prediction of neurological good and poor outcome in post-anoxic coma.

Acta neurologica Scandinavica·2016

Single electroencephalographic patterns as specific and time-dependent indicators of good and poor outcome after cardiac arrest.

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology·2016

Absent SEP during therapeutic hypothermia did not reappear after re-warming in comatose patients following cardiac arrest.

Minerva anestesiologica·2013

Thein utero initiation with DMN alters the complement of cytosolic glutathione S-transferases and the phenobarbital-induced expression ofc-jun andc-myc oncogenes in primary neonatal rat hepatocytes.

Cytotechnology·2012

See all related articles