PCBP1/HNRNP E1 Protects Chromosomal Integrity by Translational Regulation of CDC27

Abstract

Cdc27 is a core component of the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase whose oscillatory activity is responsible for the metaphase-to-anaphase transition and mitotic exit. Here, in normal murine mammary gland epithelial cells (NMuMG), Cdc27 expression is controlled post-transcriptionally through the RNA binding protein heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1/PCBP1). shRNA-mediated knockdown of hnRNP E1 abrogates translational silencing of the Cdc27 transcript resulting in constitutive expression of Cdc27. Dysregulated expression of Cdc27 leads to premature activation of the G2/M-APC/C-Cdc20 complex resulting in the aberrant degradation of Cdh1/Fzr1, a co-factor of the G1 and late G2/M-APC/C and a substrate normally reserved for the SCF-βTRCP ligase. Loss of Cdh1 expression and of APC/C-Cdh1 activity, upon constitutive expression of Cdc27, results in mitotic aberrations and aneuploidy in NMuMG cells. Further, tissue microarray (TMA) of breast cancer patient tumor samples reveals high Cdc27 levels compared to non-neoplastic breast tissue and a significant correlation between disease recurrence and Cdc27 expression. These results suggest that dysregulation of hnRNP E1-mediated translational regulation of Cdc27 leads to chromosomal instability and aneuploidy, and that Cdc27 expression represents a significant predictor of breast cancer recurrence. Implication Statement The RNA binding protein hnRNP E1 mediates translational regulation of the cell cycle regulator Cdc27 and that dysregulation of Cdc27 leads to aneuploidy. In addition, high Cdc27 expression in breast cancer patient tumor specimens significantly predicts disease recurrence, suggesting a novel role for Cdc27 as a predictor of relapse.

hnRNP E1 at the crossroads of translational regulation of epithelial-mesenchymal transition

“…The function of the PCBP1 gene encoding the hnRNP E1 protein was first demonstrated through characterization of its role as a negative regulator of alternative splicing. Since then, many additional roles have also been discovered, and most of them appear to have critical participation in the maintenance of cell phenotype integrity [34,39,67] . At the molecular level, the ability of hnRNP E1 to specifically bind to mRNA species often leads to a direct or indirect regulation of their translation.…”

Identification of Genes MediatingDrosophilaFollicle Cell Progenitor Differentiation by Screening for Modifiers of GAL4::UAS Variegation

“…Mub is a poly-C binding protein likely involved as an RNA-binding protein (Stoiber et al 2015) in posttranscriptional gene regulation, especially of splicing (Brooks et al 2015). One of its three polyC-binding, human orthologs, PCBP1, has been implicated in the translational regulation of cdc27 (Link et al 2016). …”

Decrypting the crosstalk of noncoding RNAs in the progression of IPF

“…André et al [60] revealed that BARD1, the host gene of hsa_circRNA_102910, can be involved in lung epithelial cell damage and fibroblast proliferation in IPF. The target gene of hsa_circRNA_102100 and 102101 may be related to chromosomal aneuploidy integrity and flawed cell cycles in IPF [61]. Zinc finger MYM-type 2, the host gene of hsa_circRNA _101225, can be involved in IPF by binding to fibroblast growth factor receptor1 [62].…”