Related Experiment Videos
Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation
R A Rimerman1, A Gellert-Randleman, J A Diehl
1Eppley Institute for Research in Cancer and Allied Diseases, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Abstract:
Members of the Wnt family of signal transducers regulate cellular differentiation/reorganization and cellular proliferation. However, few pro-proliferative targets of Wnt have been identified. We now show that cyclin D1, a critical mediator of cell cycle progression, is a downstream target of Wnt-dependent signaling. NIH-3T3 cell lines engineered to overexpress Wnt1 displayed reduced glycogen synthase kinase-3beta activity. Wnt1-dependent glycogen synthase kinase-3beta inhibition corresponded with decreased cyclin D1 proteolysis and, thus, hyperaccumulation of active cyclin D1.CDK4 (cyclin-dependent kinase 4) kinase. However, in the absence of serum-derived growth factors, Wnt-1 was not sufficient to drive cyclin D1 accumulation or S-phase entry. In contrast, cells engineered to co-express Wnt1 and activated MEK1 accumulated high levels of cyclin D1 and entered the DNA synthetic phase in the absence of serum-derived growth factors, a characteristic of neoplastic transformation. The ability of a dominant-negative cyclin D1 mutant, D1-T156A, to inhibit Wnt1/MEK1-dependent S-phase entry suggests that cyclin D1 is a critical downstream target for Wnt1- and MEK1-dependent cellular proliferation.
Insights
Wnt signaling regulates cell growth by targeting cyclin D1, a key cell cycle protein. This study reveals cyclin D1
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Wnt signaling pathways are crucial for cellular processes, including proliferation and differentiation.
- Identifying specific Wnt targets that promote cell proliferation is essential for understanding cancer development.
Purpose of the Study:
- To investigate whether cyclin D1 is a downstream target of Wnt signaling.
- To elucidate the role of cyclin D1 in Wnt-mediated cell cycle progression and proliferation.
Main Methods:
- Utilized NIH-3T3 cell lines engineered for Wnt1 overexpression.
- Assessed glycogen synthase kinase-3beta activity and cyclin D1 proteolysis.
- Investigated the effects of Wnt1 and activated MEK1 co-expression on cell cycle progression.
- Employed a dominant-negative cyclin D1 mutant (D1-T156A) to assess functional significance.
Main Results:
- Wnt1 overexpression reduced glycogen synthase kinase-3beta activity, leading to decreased cyclin D1 degradation and accumulation.
- Wnt1 alone was insufficient for cyclin D1 accumulation and S-phase entry without growth factors.
- Co-expression of Wnt1 and activated MEK1 induced cyclin D1 accumulation and S-phase entry independently of serum.
- A dominant-negative cyclin D1 mutant inhibited Wnt1/MEK1-driven proliferation.
Conclusions:
- Cyclin D1 is a critical downstream effector of Wnt-dependent signaling pathways.
- The Wnt1/MEK1 pathway promotes cellular proliferation through cyclin D1 accumulation, contributing to neoplastic transformation.
- Cyclin D1 is a key mediator linking Wnt signaling to cell cycle progression and proliferation.