Related Experiment Video

Updated: Aug 15, 2026

Detection of Signaling Effector-Complexes Downstream of BMP4 Using in situ PLA, a Proximity Ligation Assay
12:52

Detection of Signaling Effector-Complexes Downstream of BMP4 Using in situ PLA, a Proximity Ligation Assay

Published on: March 4, 2011

Mitogen-activated protein kinase regulates nuclear association of human progesterone receptors

Ming Qiu1, Abby Olsen, Emily Faivre

  • 1Department of Medicine, University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA.

Molecular Endocrinology (Baltimore, Md.)
|January 30, 2003
PubMed

Insights

Mitogen-activated protein kinase (MAPK) activity impacts breast cancer growth by regulating progesterone receptors (PRs). Phosphorylation of PRs at Ser294 by MAPK drives nuclear localization and influences PR stability and function.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Research

Background:

  • Increased MAPK activity is observed in breast cancers, potentially driving tumor growth by affecting steroid hormone receptors.
  • The progesterone receptor (PR) is phosphorylated by MAPK at Ser294, influencing its activity.

Purpose of the Study:

  • To investigate the role of PR Ser294 phosphorylation in subcellular distribution and its impact on PR function.
  • To elucidate the mechanism by which MAPK signaling regulates PR nuclear localization and stability.

Main Methods:

  • Stable expression of wild-type (wt) and S294A mutant PR-B in various cell types.
  • Treatment with MAPK activators, MAPK kinase inhibitor (U0126), progestin, and nuclear export inhibitor (leptomycin B).
  • Analysis of PR subcellular localization, phosphorylation status, stability, and transcriptional activity.

Main Results:

  • PRs phosphorylated at Ser294 are localized in the nucleus.
  • MAPK activation induces Ser294 phosphorylation and nuclear translocation of wt PR-B, but not S294A mutant.
  • MAPK inhibition blocks EGF-induced, but not progestin-induced, PR nuclear translocation.
  • Ligand-dependent PR degradation requires MAPK-dependent nuclear export; PR stabilization by leptomycin B inhibits transcriptional activity.

Conclusions:

  • MAPK signaling plays a critical role in regulating the subcellular localization of progesterone receptors.
  • MAPK-dependent nuclear export is essential for ligand-dependent PR degradation and influences PR transcriptional activity.
  • These findings reveal a novel regulatory mechanism linking MAPK signaling to steroid hormone receptor function in breast cancer.

More Related Videos

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 16, 2013

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

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.
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes: