Disease relevance of PABPC1

• Expression and prognostic roles of PABPC1 in esophageal cancer: correlation with tumor progression and postoperative survival [1].
• Expression of PABPC1 was quantified by real-time reverse transcription polymerase chain reaction (RT-PCR) using LightCycler in 41 primary esophageal squamous cell carcinomas (ESCCs) and their paired normal esophageal mucosa [1].
• Cleavage of poly(A)-binding protein by poliovirus 3C protease inhibits host cell translation: a novel mechanism for host translation shutoff [2].
• These results suggest that the cleavage of PABP may be another mechanism by which picornaviruses alter the rate and spectrum of protein synthesis [3].
• We have now found that PABP is also proteolytically cleaved during coxsackievirus infection of HeLa cells [3].

High impact information on PABPC1

• Rotaviruses, the cause of life-threatening diarrhea in humans and cattle, utilize a functional homolog of poly(A) binding protein (PABP) known as nonstructural protein 3 (NSP3) for translation of viral mRNAs [4].
• A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells [5].
• Interaction of polyadenylate-binding protein with the eIF4G homologue PAIP enhances translation [6].
• Pum2 also interacts with the Xenopus homolog of human Deleted for Azoospermia-like (DAZL) and the embryonic poly(A)-binding protein (ePAB) [7].
• In addition, a stronger inhibition (approximately twofold) of 80S as compared to 48S ribosome complex formation (approximately 65% vs. approximately 35%, respectively) by PABP depletion suggests that PABP plays a direct role in 60S subunit joining [8].

Biological context of PABPC1

• Here, we show that PABPC1, like the major nuclear poly(A) binding protein PABPN1, associates with nuclear pre-mRNAs that are polyadenylated and intron containing [9].
• Our findings demonstrate that PABPC1 associates with polyadenylated transcripts earlier in mammalian mRNA biogenesis than previously thought and offer insights into the mechanism by which PABPC1 is recruited to newly synthesized poly(A) [9].
• Deletion analysis identified a 29 amino acid sequence in the new N-terminal region as the PABP-binding site [10].
• The protein fragment contains a protein domain, PABC [for poly(A)-binding protein C-terminal domain], which is also found associated with the HECT family of ubiquitin ligases [11].
• Sequence profile searches and comparative protein structure modeling identified a small ORF from the Arabidopsis thaliana genome that encodes a structurally similar but distantly related PABP/HYD domain [12].

Anatomical context of PABPC1

• In contrast, PABP is constitutively expressed in both resting and activated T cells. iPABP mRNA was also expressed at much higher levels than PABP mRNA in heart and skeletal muscle tissue [13].
• Although the inhibition of the GSPT-PABP interaction did not affect the de novo formation of an 80 S ribosomal initiation complex, it appears to suppress the subsequent recycle of ribosome [14].
• Amplifications of specific DNA fragments from a human-rodent somatic cell hybrid panel have allowed us to associate PABP1 and PABP3 with 8q22 and 13q11-q12, respectively [15].
• In this work, we demonstrate that the expression of the amino-terminal one-third of eIF4G, which interacts with eIF4E and PABP, in Xenopus oocyte inhibits translation and progesterone-induced maturation [16].
• Expression of 3Cpro in HeLa cells resulted in partial PABP cleavage and similar inhibition of translation [2].

Associations of PABPC1 with chemical compounds

• The important aspect of this mechanism is that PABP binds to an adenosine-rich cis-element at the 5'-untranslated region of its own mRNA and inhibits its translation [17].
• To study the mechanism of the Paip1-PABP interaction, far-Western, glutathione S-transferase pull-down, and surface plasmon resonance experiments were performed [18].
• Binding of PABP to the RNA 5' end required the presence of the cap and was accentuated by the N7 methyl moiety of the cap [19].
• The disease is caused by the expansion of a 10-alanine stretch to 12-17 alanine residues in the poly(A)-binding protein, nuclear 1 (PABPN1; PABP2) [20].
• In mammalian cells, poly(A) binding protein C1 (PABP C1) has well-known roles in mRNA translation and decay in the cytoplasm [9].

Physical interactions of PABPC1

• PABP-interacting protein 1 (Paip1) is another factor that interacts with PABP to coactivate translation [21].
• In mammals, however, there has been no evidence that eIF4G binds PABP [10].
• The 29 amino acid stretch is almost identical in eIF4GI and eIF4GII, and the full-length eIF4GII also binds PABP [10].
• Biacore data and far-Western analysis revealed that Paip2 contains two binding sites for PABP, one encompassing a 16-amino-acid stretch located in the C terminus and a second encompassing a larger central region [22].
• Search for other GSPT-binding proteins in yeast two-hybrid screening system resulted in the identification of a cDNA encoding polyadenylate-binding protein (PABP), whose amino terminus is associating with the poly(A) tail of mRNAs presumably for their stabilization [23].

Regulatory relationships of PABPC1

• In HeLa cell translation extracts that exhibit cap-poly(A) synergy, partial cleavage of PABP by 3Cpro inhibited translation of endogenous mRNAs and reporter RNA as effectively as complete cleavage of eIF4GI and eIF4GII by 2Apro [2].
• This was confirmed by experiments where PABP was inactivated with poly(rA) or Paip2, and the effect of both treatments was reversed by addition of recombinant PABP [24].
• Dissolution of the maskin-eIF4E complex by cytoplasmic polyadenylation and poly(A)-binding protein controls cyclin B1 mRNA translation and oocyte maturation [25].
• Calicivirus 3C-like proteinase inhibits cellular translation by cleavage of poly(A)-binding protein [26].
• These data suggest that the GM-CSF ARE controls translation and mRNA decay by interfering with poly(A)-binding protein-mediated mRNA circularization [27].

Other interactions of PABPC1

• In yeast and plants, binding of eIF4G to poly(A)-binding protein (PABP) was implicated in poly(A)-dependent translation [10].
• Interaction of anti-proliferative protein Tob with poly(A)-binding protein and inducible poly(A)-binding protein: implication of Tob in translational control [28].
• A novel role of the mammalian GSPT/eRF3 associating with poly(A)-binding protein in Cap/Poly(A)-dependent translation [14].
• We also show that PABPC1 immunopurifies with poly(A) polymerase, suggesting that PABPC1 is acquired by polyadenylated transcripts during poly(A) tail synthesis [9].
• Here we studied the Paip2-PABP interaction [22].

Analytical, diagnostic and therapeutic context of PABPC1

• Co-immunoprecipitation experiments showed that the extended eIF4GI binds PABP, while the N-terminally truncated original eIF4GI cannot [10].
• We raised monoclonal antibodies against the 70-kDa hPABP and confocal immunofluorescence microscopy with these antibodies reveals that it is localized exclusively to the cytoplasm [29].
• The hPABP exhibits a very low turnover rate in these cells and quantitative immunoblotting experiments demonstrated that growing HeLa cells contain a surprisingly high number of approximately 8 x 10(6) PABP molecules per cell, which corresponds to an intracellular concentration of about 4 microM [29].
• Phosphorylation by MK2 was confirmed using PABP1 purified by affinity chromatography on poly(A) RNA [30].
• We have studied the intracellular localization of poly(A)-binding protein 1 (PABP1) by indirect immunofluorescence as well as by tagging with the green fluorescent protein (GFP) in living cells [31].

References