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The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation
Latha Shivakumar1, John Minna, Toshiyuki Sakamaki
1Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
Abstract:
The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G(1)/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G(1)/S-phase cell cycle progression.
Insights
The RASSF1A tumor suppressor inhibits cell cycle progression by regulating cyclin D1. Loss of RASSF1A function in cancer leads to uncontrolled cell division.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- The RASSF1A gene at 3p21.3 is frequently epigenetically silenced in various solid tumors.
- RASSF1A expression can reverse the tumorigenic properties of human cancer cell lines.
Purpose of the Study:
- To investigate the mechanism by which RASSF1A suppresses tumor growth.
- To determine RASSF1A's role in cell cycle regulation and its interaction with cell cycle proteins.
Main Methods:
- Cell cycle analysis in cancer cell lines with and without RASSF1A expression.
- RNA interference to downregulate endogenous RASSF1A.
- Analysis of cyclin D1 protein levels and cell cycle progression.
- Examination of rare RASSF1A alleles from tumor samples.
Main Results:
- RASSF1A induces cell cycle arrest by engaging the Rb family checkpoint.
- RASSF1A inhibits cyclin D1 accumulation post-transcriptionally, likely at the translational level.
- Ectopic expression of cyclin D1 or G1/S transition activators rescues RASSF1A-induced arrest.
- Downregulation of RASSF1A leads to abnormal cyclin D1 accumulation.
- Tumor-derived RASSF1A variants fail to inhibit cyclin D1 and cell cycle progression.
Conclusions:
- RASSF1A functions as a crucial human tumor suppressor protein.
- RASSF1A regulates the G1/S-phase transition by controlling cyclin D1 accumulation.
- Defects in RASSF1A function contribute to uncontrolled cell proliferation in cancer.