ETS-1/RhoC signaling regulates the transcription factor c-Jun in melanoma

Barbara Spangler1, Melanie Kappelmann, Birgit Schittek

  • 1Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.

Insights

Loss of E-cadherin cell adhesion increases c-Jun protein, a key factor in melanoma development. This post-transcriptional regulation involves cytoskeletal changes and signaling pathways, offering therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • E-cadherin mediates cell-cell adhesion and its loss is linked to tumor progression.
  • c-Jun (a member of the AP-1 transcription factor family) is crucial for cell proliferation and tumor development, with elevated levels in melanomas.

Purpose of the Study:

  • To elucidate the post-transcriptional regulation of c-Jun protein expression following E-cadherin loss.
  • To investigate the role of the cytoskeleton and specific signaling pathways in this process.

Main Methods:

  • Analysis of c-Jun protein and mRNA levels in relation to E-cadherin expression.
  • Investigation of the involvement of the cytoskeleton, ETS-1, and RhoC in the signaling cascade.

Main Results:

  • Loss of E-cadherin induces c-Jun protein expression without affecting its mRNA levels, indicating post-transcriptional regulation.
  • The dynamic cytoskeleton, linked to E-cadherin, regulates c-Jun protein and transcriptional activity.
  • A signaling cascade involving ETS-1 and RhoC, indirectly via the cytoskeleton, stabilizes c-Jun in melanoma cells.

Conclusions:

  • E-cadherin loss-mediated cell-adhesion induces c-Jun protein expression through a multistep process.
  • The identified pathway involving the cytoskeleton, ETS-1, and RhoC presents potential therapeutic intervention points for melanoma.

Related Concept Videos

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...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
Hedgehog Signaling Pathway02:33

Hedgehog Signaling Pathway

The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...