c-Jun can mediate androgen receptor-induced transactivation

A Bubulya1, S C Wise, X Q Shen

  • 1Department of Biology, University of Toledo, Toledo, Ohio 43606, USA.

Insights

The proto-oncoprotein c-Jun indirectly regulates androgen receptor (AR) activity without binding DNA or interacting with c-Fos. c-Jun enhances AR-mediated transcription, suggesting a novel mediator role in gene regulation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The proto-oncoprotein c-Jun typically heterodimerizes with c-Fos to form the transcription factor AP-1.
  • AP-1 regulates gene transcription through DNA binding and transactivation.
  • The androgen receptor (AR) is a key regulator of gene expression, particularly in prostate cancer.

Purpose of the Study:

  • To investigate a novel, indirect mechanism by which c-Jun regulates transcription via the androgen receptor.
  • To determine if c-Jun can influence AR-mediated transactivation independently of c-Fos or DNA binding.

Main Methods:

  • Utilized a modified yeast two-hybrid system in Cos cells to assess protein interactions.
  • Performed dose-response and time-course experiments to evaluate c-Jun's effect on AR activity.
  • Investigated the impact of c-Fos on AR and c-Jun interactions.

Main Results:

  • c-Jun supports AR-mediated transactivation independently of c-Fos or direct DNA binding.
  • The positive effect of c-Jun on AR activity is dose-dependent.
  • c-Jun interacts with the DNA binding/hinge region of the androgen receptor.
  • c-Jun relieves AR self-squelching and its effect is primary, preceding c-Fos interference.

Conclusions:

  • c-Jun acts as a mediator for androgen receptor-induced transactivation through a novel indirect mechanism.
  • This finding reveals a new regulatory pathway for AR activity, potentially impacting cancer biology.
  • c-Jun's interaction with the AR's CD regions is crucial for this mediating function.

Related Concept Videos

Internal Receptors01:31

Internal Receptors

Many cellular signals are hydrophilic and therefore cannot pass through the plasma membrane. However, small or hydrophobic signaling molecules can cross the hydrophobic core of the plasma membrane and bind to internal, or intracellular, receptors that reside within the cell. Many mammalian steroid hormones use this mechanism of cell signaling, as does nitric oxide (NO) gas.
RNA Polymerase II Accessory Proteins02:36

RNA Polymerase II Accessory Proteins

Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
Co-activators and Co-repressors02:04

Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...