Key result
Overexpression of Sam68 in fibroblasts induced cell cycle arrest independently of its RNA binding ability, whereas its induction of apoptosis strictly required a functional RNA binding domain.
Absolute Event Rate: 24% vs 89%
Sam68 exerts functionally separable effects on cell proliferation and survival, with apoptosis specifically requiring its RNA binding ability.
Domain-specific Sam68 targeting may enable selective modulation of fibroblast proliferation versus apoptosis; hypothesis-generating and leaves open cardiovascular translation.
BACKGROUND: The RNA-binding protein Sam68 has been implicated in a number of cellular processes, including transcription, RNA splicing and export, translation, signal transduction, cell cycle progression and replication of the human immunodeficiency virus and poliovirus. However, the precise impact it has on essential cellular functions remains largely obscure. RESULTS: In this report we show that conditional overexpression of Sam68 in fibroblasts results in both cell cycle arrest and apoptosis. Arrest in G1 phase of the cell cycle is associated with decreased levels of cyclins D1 and E RNA and protein, resulting in dramatically reduced Rb phosphorylation. Interestingly, cell cycle arrest does not require the specific RNA binding ability of Sam68. In marked contrast, induction of apoptosis by Sam68 absolutely requires a fully-functional RNA binding domain. Moreover, the anti-cancer agent trichostatin A potentiates Sam68-driven apoptosis. CONCLUSIONS: For the first time we have shown that Sam68, an RNA binding protein with multiple apparent functions, exerts functionally separable effects on cell proliferation and survival, dependent on its ability to bind specifically to RNA. These findings shed new light on the ability of signal transducing RNA binding proteins to influence essential cell function. Moreover, the ability of a class of anti-cancer therapeutics to modulate its ability to promote apoptosis suggests that Sam68 status may impact some cancer treatments.
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Taylor et al. (2004) studied this question. Sam68 overexpression vs. Uninduced cells or cells expressing RNA binding-defective Sam68 was evaluated on BrdU positive cells 24 hours after release from mitosis (indicating G1 to S phase progression). Overexpression of Sam68 in fibroblasts induced cell cycle arrest independently of its RNA binding ability, whereas its induction of apoptosis strictly required a functional RNA binding domain.
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