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Related Experiment Videos

Conditional apoptosis induced by oncogenic ras in thyroid cells.

J M Shirokawa1, R Elisei, J A Knauf

  • 1Department of Medicine, University of Cincinnati College of Medicine, Ohio 45267-0547, USA.

Molecular Endocrinology (Baltimore, Md.)
|November 15, 2000
PubMed
Summary

Oncogenic Ras activation in thyrocytes triggers apoptosis, particularly when cAMP signaling is also active. Surviving cells may lose TSH responsiveness, enabling tumor growth.

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Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Endocrinology

Background:

  • Ras mutations are key tumor-initiating events in various cell types, including thyroid cells (thyrocytes).
  • Understanding the early cellular responses to oncogenic Ras activation is crucial for cancer research.

Purpose of the Study:

  • To investigate the immediate consequences of oncogenic Ras signaling in rat thyroid PCCL3 cells.
  • To elucidate the roles of mitogen-activated protein kinase kinase (MEK1), extracellular ligand-regulated kinase (ERK), and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) pathways in Ras-induced apoptosis.
  • To determine the influence of cAMP signaling on Ras-mediated thyrocyte fate.

Main Methods:

  • Development of a doxycycline-inducible expression system for oncogenic H-Ras(v12) in PCCL3 cells.

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  • Utilized MEK1 inhibitors and activated MEK1 mutants to study pathway involvement.
  • Investigated apoptosis induction via Rac1(v12) to assess SAPK/JNK pathway roles.
  • Examined the dependency of apoptosis on cAMP activation by thyroid-stimulating hormone (TSH) or forskolin.

    • Main Results:

    • Expression of H-Ras(v12) in PCCL3 cells induced apoptosis within 3-4 days.
    • Apoptosis was partially mediated by MEK1 and ERK activation.
    • SAPK/JNK pathway activation also triggered apoptosis without causing genomic instability.
    • H-Ras(v12)-induced apoptosis required simultaneous cAMP pathway activation (TSH or forskolin) in a protein kinase A-independent manner.
    • Co-activation of Ras and cAMP pathways led to cell death, while survivors exhibited altered TSH responsiveness.

    Conclusions:

    • Simultaneous activation of Ras and cAMP signaling pathways is detrimental to thyrocyte survival.
    • Thyrocyte fate following oncogenic Ras expression is contingent on ambient cAMP levels.
    • Thyrocytes that survive Ras activation may undergo secondary events, leading to loss of TSH responsiveness and potential clonal expansion, contributing to tumor development.