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Expression of c-Myc in response to colony-stimulating factor-1 requires mitogen-activated protein kinase kinase-1
1Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Abstract:
The mitogen-inducible gene c-myc is a key regulator of cell proliferation and transformation. Yet, the signaling pathway(s) that regulate its expression have remained largely unresolved. Using the mitogen-activated protein kinase kinase (MEK1/2) inhibitor PD98059 and dominant negative forms of Ras (N17) and ERK1 (K71R), we found that activation of Ras and extracellular signal-regulated kinase (ERK) is necessary for colony-stimulating factor-1 (CSF-1)-mediated c-Myc expression and DNA synthetic (S) phase entry. Quiescent NIH-3T3 cells expressing a partially defective CSF-1 receptor, CSF-1R (Y809F), exhibited impaired ERK1 activation and c-Myc expression and failed to enter the S phase of the cell division cycle in response to CSF-1 stimulation. Ectopic expression of a constitutively active form of MEK1 in cells expressing CSF-1R (Y809F) rescued c-Myc expression and S phase entry, but only in the presence of CSF-1-induced cooperating signals. Therefore, MEK1 participates in an obligate signaling pathway linking CSF-1R to c-Myc expression, but other signals from CSF-1R must cooperate with the MEK/ERK pathway to induce c-Myc expression and S phase entry in response to CSF-1 stimulation.
Insights
Ras and extracellular signal-regulated kinase (ERK) activation are essential for colony-stimulating factor-1 (CSF-1)-mediated c-Myc expression and cell cycle entry. The MEK/ERK pathway is critical but requires cooperating signals for full c-Myc induction.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- The c-Myc gene is crucial for cell proliferation and transformation.
- Signaling pathways regulating c-Myc expression are not fully understood.
Purpose of the Study:
- To elucidate the signaling pathways regulating c-Myc expression in response to CSF-1.
- To determine the role of Ras/ERK pathway in CSF-1-mediated c-Myc induction and cell cycle progression.
Main Methods:
- Utilized MEK1/2 inhibitor PD98059 and dominant-negative Ras (N17) and ERK1 (K71R).
- Investigated c-Myc expression and S phase entry in NIH-3T3 cells with wild-type and mutant CSF-1 receptors (CSF-1R).
- Employed ectopic expression of constitutively active MEK1.
Main Results:
- Ras and ERK activation are necessary for CSF-1-induced c-Myc expression and S phase entry.
- Mutant CSF-1R (Y809F) impaired ERK1 activation, c-Myc expression, and S phase entry.
- Constitutively active MEK1 rescued c-Myc expression and S phase entry in mutant cells, but required cooperating signals.
Conclusions:
- MEK1 is part of an essential pathway linking CSF-1R to c-Myc expression.
- Cooperating signals from CSF-1R are necessary alongside the MEK/ERK pathway for c-Myc induction and S phase entry.