Research In The Nuclear Function Of Eukaryotic MRNA Poly(A)-binding Protein PABP1

PABP1 is one of eukaryotic mRNA Poly(A)-binding protein family members. It mainly functions in the regulation of mRNA translation and stability, and plays a critical role in mRNA processing, transport, turnover, and decay. PABP1 is a nuclear-cytoplasmic shuttling protein. In normal condition, PABP1 is predominantly cytoplasmic. However it accumulates dramatically in the nucleus in response to some cellular stresses such as oxidative stress, heat shock, and UV radiation. It is less known about the mechanism which PABP1 shuttles to the nucleus and the nuclear function of PABP1.Here, we show that PABP1 can affect the protein level of oncoprotein MDM2, a RING finger E3 ligase primarily known for its role in controlling P53 stability. To investigate the molecular basis of this effect, we examined whether PABP1 can interact with MDM2 and studied the specific molecular mechanism. Our results show that PABP1 binds to MDM2 and regulates the protein level of MDM2 through affecting MDM2 self-ubiquitination, not involved in the transcription of MDM2. It is well-known that tumor suppressor P53 is a target protein of MDM2. MDM2 can promote the degradation of P53 through the ubiqutin-proteasome pathway, and inhibit the apoptosis of tumor cell. PABP1 shuttles and accumulates in the nucleus upon cellular stresses, which may be trough a phosphorylation dependent manner. We find that the interaction between PABP1 and MDM2 enhances. PABP1 can promote the degradation of MDM2, disturb the binding of MDM2and P53, attenuate the degradation to P53, and further affect the transcriptional activity of P53 and the function of P53 in inducing cell apoptosis.Our results suggest that PABP1 is a new MDM2 regulator, and provide a firm theory foundation for the nuclear function of PABP1 and the mechanism involved in tumor suppression.