Translation Regulation during Mitotic Phase
- Title
- Translation Regulation during Mitotic Phase
- Authors
- 안시현
- Date Issued
- 2020
- Publisher
- 포항공과대학교
- Abstract
- Translation is mediated by numerous factors and serve as a key regulatory
pathway of gene expression for living organisms. Regulation of translation is
provoked by various cellular responses such as external stimuli, differentiation, and
proliferation. The general translation in eukaryotes are controlled in several ways:
eIF2a phosphorylation, 4E-BP phosphorylation, mTOR signalling, etc.
During mitosis, translation of most mRNAs is strongly repressed. Several
hypotheses have been suggested to explain this interesting phenomenon, but none of
them fully explains the molecular basis of the translational repression. Here I report a
cyclin-dependent CDK11/p58, which is a serine/threonine kinase expressed in large
quantity only in M phase, represses general translation through phosphorylation of a
subunit (eIF3F) of translation factor eIF3 complex that is essential for translation
initiation of most mRNAs. Ectopic expression of CDK11/p58 strongly repressed capdependent
translation, and knockdown of CDK11/p58 nullified the translational
repression at the M phase. I identified the phosphorylation sites in the eIF3F
responsible for the M phase-specific translational repression by CDK11/p58. Alanine
substitutions of the CDK11/p58 target sites in the eIF3F nullified the cell cycledependent
translational regulation. Considering that the conservation of CDK11 and
the target sites on the eIF3F from C. elegans to human, I speculate that the mechanism
of translational regulation by a M phase-specific kinase CDK11 has deep evolutionary
roots.
eIF4GII is referred as just a functional homolog of eIF4GI in mammals, despite
their considerable amino acid sequence differences. Here I suggest novel aspects
about differences between eIF4GI and eIF4GII in eIF4F complex formation manner.
eIF4GII showed higher affinity than eIF4GI in interactions with eIF4E or mRNA 5’
cap. When mTORC1 is inactivated by rapamycin treatment, eIF4GI largely lost its
interaction with eIF4E while eIF4GII to eIF4E interaction was sustained. Besides,
amino acid starvation or hypoxia driven ER stresses provoked similar phenomena as
rapamycin treatment. Interestingly, global translation was no further inhibited during
knockdown of eIF4GII in stress conditions, indicating eIF4GII may be related to the
translation of specific mRNAs. Moreover, the ratio of eIF4GII association to cap
binding complex was increased during neuronal differentiation. Therefore, here I
propose that an alternative core protein of eIF4F complex, eIF4GII, drives specific
mRNA translation during ER stress and neuron differentiation.
In summary, I investigated the molecular basis of general translation control
mechanisms in mitosis and stress condition. I showed eIF3F phosphorylation occurs
in mitotic phase by CDK11/p58 and its phosphorylation is a key process on mitotic
translational repression. I also propose the eIF4GII dependent translation which is
provoked in stress and developmental conditions. I believe that these studies provide
the novel mechanism of mitotic translational repression and eIF4GII dependent
translation.
- URI
- http://postech.dcollection.net/common/orgView/200000332886
https://oasis.postech.ac.kr/handle/2014.oak/111521
- Article Type
- Thesis
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