Indiana University-Purdue University Indianapolis (IUPUI) / Gene expression is a highly coordinated process that relies upon appropriate
regulation of translation for protein homeostasis. Regulation of protein synthesis largely
occurs at the initiation step in which the translational start site is selected by ribosomes
and associated initiating factors. In addition to the coding sequences (CDS) for protein
products, short upstream open reading frames (uORFs) located in the 5’-leader of
mRNAs are selected for translation initiation. While uORFs are largely considered to be
inhibitory to translation at the downstream CDS, uORFs can also promote initiation of
CDS translation in response to environmental stresses. Multiple transcripts associated
with stress adaptation are preferentially translated through uORF-mediated mechanisms
during activation of the Integrated Stress Response (ISR). In the ISR, phosphorylation
of α subunit of the translation initiation factor eIF2α (eIF2α~P) during environmental
stresses results in a global reduction in protein synthesis that functions to conserve
energy and nutrient resources and facilitate reprogramming of gene expression.
Many key regulators of the ISR network are subject to preferential translation in
the response to eIF2α-P. These preferentially translated genes include the pro-apoptotic
transcriptional activator Chop that modifies gene expression programs, feedback
regulator Gadd34 that targets the catalytic subunit of protein phosphatase 1 to
dephosphorylate eIF2α~P, and glutamyl-prolyl tRNA synthetase Eprs that increases the
charged tRNA pool and primes the cell for resumption of protein synthesis after stress
remediation. Ribosome bypass of at least one inhibitory uORF is a common theme
between Chop, Gadd34, and Eprs, which allows for their regulated expression in
response to cellular stress. However, different features encoded within the uORFs of the Chop, Gadd34, and Eprs mRNAs provide for regulation of their inhibitory functions,
illustrating the complexities of uORF-mediated regulation of gene-specific translation.
Importantly, preferentially translated ISR targets can also be transcriptionally regulated
in response to cellular stress and misregulation of transcriptional or translational
expression of Gadd34 can elicit maladaptive cell responses that contribute to disease.
These mechanisms of translation control are conserved throughout species,
emphasizing the importance of translation control in appropriate gene expression and
the maintenance of protein homeostasis and health in diverse cellular conditions.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/10606 |
| Date | 13 May 2016 |
| Creators | Young, Sara Kathryn |
| Contributors | Wek, Ronald C. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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