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AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation.

ABSTRACT: In the present study, we investigated the 3' untranslated region (UTR) of the mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3'UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3'UTR is widely known to function as a cis-acting element of mRNA degradation. The 3'UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds to the Cry1 3'UTR and regulates translation of Cry1 mRNA. AUF1 interacted with eukaryotic translation initiation factor 3 subunit B and also directly associated with ribosomal protein S3 or ribosomal protein S14, resulting in translation of Cry1 mRNA in a 3'UTR-dependent manner. Expression of cytoplasmic AUF1 and binding of AUF1 to the Cry1 3'UTR were parallel to the circadian CRY1 protein profile. Our results suggest that the 3'UTR of Cry1 is important for its rhythmic translation, and AUF1 bound to the 3'UTR facilitates interaction with the 5' end of mRNA by interacting with translation initiation factors and recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA.

SUBMITTER: Lee KH

PROVIDER: S-EPMC3973335 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation.

Lee Kyung-Ha KH Kim Sung-Hoon SH Kim Hyo-Jin HJ Kim Wanil W Lee Hwa-Rim HR Jung Youngseob Y Choi Jung-Hyun JH Hong Ka Young KY Jang Sung Key SK Kim Kyong-Tai KT

Nucleic acids research 20140113 6

In the present study, we investigated the 3' untranslated region (UTR) of the mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level, particularly its translational regulation. Interestingly, the 3'UTR of Cry1 mRNA decreased its mRNA levels but increased protein amounts. The 3'UTR is widely known to function as a cis-acting element of mRNA degradation. The 3'UTR also provides a binding site for microRNA and mainly suppresses translation of target mRNAs. We found that AU-ri ...[more]

PMID: 24423872

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Project description:BACKGROUND:Alveologenesis is the final stage of lung development to form air-exchanging units between alveoli and blood vessels. Genetic susceptibility or hyperoxic stress to perturb this complicated process can cause abnormal enlargement of alveoli and lead to bronchopulmonary dysplasia (BPD)-associated emphysema. Platelet-derived growth factor receptor ? (PDGFR?) signaling is crucial for alveolar myofibroblast (MYF) proliferation and its deficiency is associated with risk of BPD, but posttranscriptional mechanisms regulating PDGFR? synthesis during lung development remain largely unexplored. Cytoplasmic polyadenylation element-binding protein 2 (CPEB2) is a sequence-specific RNA-binding protein and translational regulator. Because CPEB2-knockout (KO) mice showed emphysematous phenotypes, we investigated how CPEB2-controlled translation affects pulmonary development and function. METHODS:Respiratory and pulmonary functions were measured by whole-body and invasive plethysmography. Histological staining and immunohistochemistry were used to analyze morphology, proliferation, apoptosis and cell densities from postnatal to adult lungs. Western blotting, RNA-immunoprecipitation, reporter assay, primary MYF culture and ectopic expression rescue were performed to demonstrate the role of CPEB2 in PDGFR? mRNA translation and MYF proliferation. RESULTS:Adult CPEB2-KO mice showed emphysema-like dysfunction. The alveolar structure in CPEB2-deficient lungs appeared normal at birth but became simplified through the alveolar stage of lung development. In CPEB2-null mice, we found reduced proliferation of MYF progenitors during alveolarization, abnormal deposition of elastin and failure of alveolar septum formation, thereby leading to enlarged pulmonary alveoli. We identified that CPEB2 promoted PDGFR? mRNA translation in MYF progenitors and this positive regulation could be disrupted by H2O2, a hyperoxia-mimetic treatment. Moreover, decreased proliferating ability in KO MYFs due to insufficient PDGFR? expression was rescued by ectopic expression of CPEB2, suggesting an important role of CPEB2 in upregulating PDGFR? signaling for pulmonary alveologenesis. CONCLUSIONS:CPEB2-controlled translation, in part through promoting PDGFR? expression, is indispensable for lung development and function. Since defective pulmonary PDGFR signaling is a key feature of human BPD, CPEB2 may be a risk factor for BPD.

Dataset Information

AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation.

Publications

AUF1 contributes to Cryptochrome1 mRNA degradation and rhythmic translation.

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