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transcription, RNA polymerase inhibition results in the cytoplasmic accumulation of many splicing factors.
[32]
Such observations support the primordial nuclear role of hnRNP E1 in pre-RNA splicing . The subcellular
localization of hnRNP E1 is also governed by cell signaling stimuli. It was demonstrated that SMAD3
and hnRNP E1 were induced to govern alternative splicing, mediated by their colocalization in SC35 (also
[33]
known as SRSF2)-positive nuclear speckles, downstream of EGF and TGFb, respectively . Even if it is to a
lesser extent, hnRNP E1 is also clearly observed in the cytoplasm, and its presence potentially correlates to
its function as a translational regulator [29,34,35] .

REGULATION OF TRANSCRIPTION
HnRNP E1 functions as a regulator of gene expression at the transcriptional level, although this does not
appear to be its primary role. Recombinant cloning of the four members (PCBP1 to PCBP4) of the poly(C)
binding protein family (PCBP) demonstrated that transcriptional activity of the mouse μ-opioid receptor
(MOR) gene increased due to interaction between PCBPs and the 26-bp polypyrimidine stretch in the MOR
[36]
[27]
proximal promoter . PCBPs can bind either to single-stranded or to double-stranded DNA . hnRNP
[37]
E1 also exhibits a mild but consistent activation of the promoter of the BRCA1 gene . Finally, hnRNP E1
[38]
was found to regulate eIF4E transcription . Recruitment of hnRNP E1 to the eIF4E basal element (4EBE)
in the eIF4E promoter region occurs downstream of serum or EGF-mediated cellular stimulation, and this
[38]
mechanism requires Pak1-dependent phosphorylation of hnRNP E1 protein . These findings suggest that
both hnRNP E1 and its phosphorylation downstream of growth factor-induced signaling play a regulatory
role in eIF4E transcription in mitogen-stimulated cells.

TRANSLATION REGULATION
The hnRNP E1 protein regulates translation through either direct or indirect mechanisms. Examples of the
most common mechanisms include regulation of mRNA stability, direct control of the ribosomal machinery,
or the generation of RNA species that prevent miRNA-mediated translational repression of specific mRNAs.

Control of mRNA stability
The role of hnRNP E1 in RNA stability is exemplified by a broad spectrum of mRNA interactions. Mainly,
hnRNP E1 regulates gene expression via binding to specific AU-rich elements (AREs) or U-rich elements
located in the 3’ untranslated regions (UTR) of target mRNAs. For instance, the binding of hnRNP E1 to
kip1
kip1
kip1
p27 3’ UTR via its KH1 domain stabilizes p27 mRNA, fueling p27 protein expression by enhancing
kip1
its translation prior to degradation. The upregulated p27 protein consequently inhibits cell proliferation,
cell cycle progression, and tumorigenesis, and can concurrently promote cell apoptosis under paclitaxel
[39]
treatment . Interestingly, other cyclin-dependent kinase inhibitors such as p21 Waf1 are also regulated
through hnRNP E1 mediated mRNA stability. Co-immunopurification of p21 Waf1 mRNA from MDA-
MB-468 breast cancer cells using hnRNP E1 antibody suggests that hnRNP E1 protein binds to one or more
Waf1
[30]
motifs distributed throughout the p21 3’ UTR to stabilize the mRNA .
The eNOS mRNA 3’ UTR contains multiple evolutionarily conserved pyrimidine (C and CU)-rich sequence
elements that are both necessary and sufficient for mRNA stabilization. The hnRNP E1 protein binds to
these 3’ UTR elements. Hence, hnRNP E1is recruited to a stabilizing RNP complex that protects eNOS
mRNA from the inhibitory effects of its antisense transcript sONE, and from 3’ UTR-targeting small
[40]
interfering RNAs (siRNAs) and miRNAs . HnRNP E1 regulates the stability of p63 mRNA via binding
[41]
to a CU-rich element (CUE) within the p63 3’ UTR . The p63 protein contribution to EMT could vary
according to the biological context. It has been shown that p63 directly modulates the tumor cell plasticity by
either attenuating EMT in human prostate cancer cells or promoting tumor cell invasion during human and
mouse breast tumor cells dissemination [42,43] . Phosphorylation of hnRNP E1 also contributes to stabilization