The nuclear receptor NR2E1/TLX controls senescence.
Ana O'Loghlen1,2, Nadine Martin1, Benjamin Krusche3
1Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
Oncogene
|October 21, 2014
Summary
The nuclear receptor NR2E1 (also known as TLX) regulates neural stem cell self-renewal and brain tumor initiation by controlling senescence and polycomb repressive complexes, notably CBX7.
Area of Science:
- Molecular Biology
- Stem Cell Biology
- Cancer Research
Background:
- The nuclear receptor NR2E1 (TLX) is crucial for neural stem cell (NSC) self-renewal and implicated in brain tumor development.
- Existing knowledge on NR2E1's role in NSC self-renewal and tumorigenesis is incomplete, particularly regarding its connection to polycomb repressive complexes (PRCs).
Purpose of the Study:
- To investigate the regulatory relationship between NR2E1 and PRCs.
- To elucidate the mechanisms underlying NR2E1's function in NSC self-renewal and tumorigenesis, focusing on senescence and polycomb action.
Main Methods:
- Screening for transcription factors regulating CBX7 expression.
- Analyzing NR2E1 binding to the CBX7 promoter.
- Assessing the impact of NR2E1 and CBX7 on cellular senescence.
- Evaluating NR2E1 and CBX7 expression in human glioblastoma samples.
Main Results:
- NR2E1 directly binds to and induces the expression of CBX7, a component of PRCs.
- A feedback loop exists where CBX7 represses NR2E1.
- NR2E1 inhibits cellular senescence and extends cell lifespan by regulating p16(INK4a) and repressing p21(CIP1).
- NR2E1 knockdown induces premature senescence in human cells and NSCs.
- NR2E1 expression positively correlates with CBX7 expression in glioblastoma.
Conclusions:
- NR2E1 regulates CBX7, linking NR2E1 to polycomb repressive complex function.
- NR2E1's role in restraining senescence is a key mechanism in NSC self-renewal and cancer suppression.
- These findings provide novel insights into NR2E1's multifaceted roles in stem cell biology and oncogenesis.
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