PABPC1——mRNA stability, protein translation and tumorigenesis

Abstract

Mammalian poly A-binding proteins (PABPs) are highly conserved multifunctional RNA-binding proteins primarily involved in the regulation of mRNA translation and stability, of which PABPC1 is considered a central regulator of cytoplasmic mRNA homing and is involved in a wide range of physiological and pathological processes by regulating almost every aspect of RNA metabolism. Alterations in its expression and function disrupt intra-tissue homeostasis and contribute to the development of various tumors. There is increasing evidence that PABPC1 is aberrantly expressed in a variety of tumor tissues and cancers such as lung, gastric, breast, liver, and esophageal cancers, and PABPC1 might be used as a potential biomarker for tumor diagnosis, treatment, and clinical application in the future. In this paper, we review the abnormal expression, functional role, and molecular mechanism of PABPC1 in tumorigenesis and provide directions for further understanding the regulatory role of PABPC1 in tumor cells.

Homeostasis of mRNA concentrations through coupling transcription, exportation, and degradation

“…Recently, Gilbertson et al showed that in mammalian cells, the poly(A)-binding protein cytoplasmic 1 (PABPC1) plays a critical role in this process [41]. PABPC1 is an RBP that binds directly to the poly(A) tail of the pre-mRNA in the nucleus and is released in the cytoplasm after mRNA is degraded, functioning in mRNA translation and degradation [56–58]. Researchers found that it also interferes with the formation of PIC in the nucleus [41].…”

Positioning determines function: Wandering PKM2 performs different roles in tumor cells

“…As its name suggests, RBP is a kind of protein that binds with RNA. Having a variety of regulatory, structural, and catalytic roles, functional RNA interacts with proteins to conduct functions in the cell, such as processing, transport, translation, RNA stabilization, modification, and localization (Hashimoto & Kishimoto, 2022; Qi et al, 2022; Smith & Costa, 2022). Examples supporting these abound.…”

Direct and indirect consequences ofPAB1deletion in the regulation of translation initiation, translation termination, and mRNA decay

“…The numerous functions of PABPC are attributed to its ability to interact with not only mRNAs but also various other proteins to form messenger ribonucleoprotein (mRNP) complexes [2]. PABPC's conserved structure consists of three regions: i) four RNA recognition motif (RRM) domains, two of which (RRM1 and RRM2) bind 12 adenosines with high affinity [3,4], while the protein overall covers 27 adenosines [5], ii) a proline-rich (P) linker domain, and iii) a C-terminal mademoiselle (MLLE) domain that interacts with other proteins via their PABP-interacting motif 2 (PAM2) [2,3,6]. Mammals have multiple isoforms of PABPCs, of which the most ubiquitous isoform as well as the most studied is PABPC1, whereas the yeast Saccharomyces cerevisiae has only one PABPC, Pab1 [2,3,6,7].…”

“…Current elaborations of this model postulate that mRNAs could be circularized by a chain of interactions between poly(A)-associated PABPC and 5' end-localized initiation factors, giving rise to a poly(A) tail-PABPC-eIF4G-eIF4E-5'cap network [2,[26][27][28][29][30]. eIF4G has been shown to interact with PABPC's RRM2 domain [26,[31][32][33], and disrupting this interaction reduced translation [6,29,34]. Thus, PABPC can stabilize the cap-binding complex and aid the recruitment of the 43S preinitiation complex to the mRNA [2,3,35].…”

“…In addition to its interactions with initiation factors, PABPC also interacts with the release factor eRF3 via its PAM2 motif in metazoans and its P-C domains in yeast [2,6,[41][42][43][44]. Translation termination involves stop codon recognition in the ribosomal Asite and nascent peptide release by eRF1, whose hydrolysis function and conformational change are stimulated by eRF3's GTPase activity [45,46].…”