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JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression
1Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Abstract:
A role for the transcription factor JunB in proliferation control was investigated in genetically modified mouse fibroblasts. Increased JunB expression induced high levels of the cyclin-dependent kinase inhibitor p16(INK4a), leading to premature senescence in primary cells and reduced proliferation in 3T3 cells, whereas lack of JunB expression results in decreased p16 levels. Furthermore, JunB-mediated p16 induction in 3T3 cells completely abolished cyclin D-associated kinase activity, resulting in reduced pRb hyperphosphorylation and G(1)-phase extension. Moreover, three AP1-like binding sites were identified in the p16 promoter through which JunB directly activates p16 transcription. Elevated JunB expression in 3T3 cells also inhibited Ras- and Src-mediated transformation and tumour growth in vivo. The suppressive effect of JunB on cell proliferation was shown to be dependent on p16 since it did not occur in INK4a(-/-) fibroblasts that lack both p16 and p19(ARF). These results demonstrate that p16 is a direct transcriptional target gene of JunB and identify JunB as a negative regulator of cell proliferation.
Insights
JunB transcription factor controls cell proliferation by regulating p16INK4a. Increased JunB induces p16INK4a, causing senescence and inhibiting tumor growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- JunB is a transcription factor involved in cellular processes.
- The regulation of cell proliferation is crucial for preventing uncontrolled growth and cancer.
- p16INK4a is a key inhibitor of cyclin-dependent kinases that promotes cell cycle arrest.
Purpose of the Study:
- To investigate the role of the transcription factor JunB in controlling cell proliferation.
- To determine if JunB directly regulates the expression of p16INK4a.
- To elucidate the mechanism by which JunB affects cell cycle progression and tumor growth.
Main Methods:
- Genetically modified mouse fibroblasts (primary and 3T3 cell lines) were used.
- JunB expression levels were manipulated (increased or decreased).
- p16INK4a levels, cyclin-dependent kinase activity, pRb hyperphosphorylation, and cell proliferation were assessed.
- Analysis of JunB binding sites in the p16 promoter was performed.
- Ras- and Src-mediated transformation and tumor growth in vivo were evaluated.
- Experiments were conducted in INK4a(-/-) fibroblasts lacking p16 and p19(ARF).
Main Results:
- Increased JunB expression led to elevated p16INK4a levels, causing premature senescence and reduced proliferation.
- Lack of JunB expression resulted in decreased p16INK4a levels.
- JunB-mediated p16INK4a induction abolished cyclin D-associated kinase activity, reduced pRb hyperphosphorylation, and extended the G1 phase.
- Three AP1-like binding sites in the p16 promoter were identified, demonstrating JunB's direct transcriptional activation of p16.
- Elevated JunB inhibited Ras- and Src-mediated transformation and tumor growth in vivo.
- The suppressive effect of JunB on proliferation was dependent on p16INK4a, as it was absent in INK4a(-/-) fibroblasts.
Conclusions:
- p16INK4a is a direct transcriptional target of JunB.
- JunB acts as a negative regulator of cell proliferation.
- JunB's role in proliferation control is mediated through the induction of p16INK4a.
- JunB has potential as a tumor suppressor by inhibiting cell transformation and growth.