During aging, organisms show altered gene expression patterns and have an increasingly impaired ability to respond to stress-causing and mitogenic stimuli. Since post-transcriptional processes critically regulate changes in the collections of expressed proteins, it is extremely important to elucidate the microRNAs (as well as RBPs, as described in other projects) that control age-related gene expression patterns. To investigate microRNA function during senescence, we employ approaches such as microRNA reduction (by transfecting an antisense RNA), microRNA overexpression (by transfecting a precursor of the microRNA), and the identification of microRNA-associated mRNAs by transfecting biotinylated microRNAs and identifying target mRNAs through various methods (eg, microarray, RT-PCR). We investigate whether microRNAs affect the stability of target mRNAs during senescence by measuring the steady-state levels and half-lives of the mRNAs of interest as a function of microRNA abundance. We investigate whether microRNAs affect the translation of target mRNAs by modulating microRNA levels, and subsequently studying the relative assocation of the mRNA with translating polysomes and by quantifying the nascent translation rates of the encoded proteins. We also employ reporter constructs to gain additional insight into the processes modulated by microRNAs and use different senescence-associated markers to examine changes in the senescence phenotype. During the past funding period, we have reported that in human diploid fibroblasts the microRNA miR-519 plays a central role in the implementation of replicative senescence (Marasa et al., Aging, 2010). We also discovered that miR-519 triggers senescence at least in part by lowering expression levels of the RBP HuR (Abdelmohsen et al., Cell Cycle, 2010). We also participated in collaborative efforts with the Evans laboratory to identify differences in microRNA expression patterns as a function of age (Noren et al., PLoS ONE, 2010). Ongoing studies are analyzing systematically the target mRNAs of biotinylated microRNAs whose levels decline or increase with senescence. There is also a great deal of interest in elucidating other noncoding RNA with roles in cellular senescence and aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000394-04
Application #
8335856
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$431,271
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Kim, Kyoung Mi; Abdelmohsen, Kotb; Mustapic, Maja et al. (2017) RNA in extracellular vesicles. Wiley Interdiscip Rev RNA 8:
Kim, Kyoung Mi; Noh, Ji Heon; Abdelmohsen, Kotb et al. (2017) Mitochondrial noncoding RNA transport. BMB Rep 50:164-174
Kim, Chongtae; Lee, Heejin; Kang, Hoin et al. (2016) RNA-binding protein HuD reduces triglyceride production in pancreatic ? cells by enhancing the expression of insulin-induced gene 1. Biochim Biophys Acta 1859:675-85
Noh, Ji Heon; Kim, Kyoung Mi; Abdelmohsen, Kotb et al. (2016) HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP. Genes Dev 30:1224-39
Kim, Jiyoung; Kim, Kyoung Mi; Noh, Ji Heon et al. (2016) Long noncoding RNAs in diseases of aging. Biochim Biophys Acta 1859:209-21
Lastres-Becker, Isabel; Nonis, David; Eich, Florian et al. (2016) Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation. Biochim Biophys Acta 1862:1558-69
Scheibye-Knudsen, Morten; Tseng, Anne; Borch Jensen, Martin et al. (2016) Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. Proc Natl Acad Sci U S A 113:12502-12507
Di Francesco, Andrea; Di Germanio, Clara; Panda, Amaresh C et al. (2016) Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation. Free Radic Biol Med 99:225-233
Panda, Amaresh C; Abdelmohsen, Kotb; Martindale, Jennifer L et al. (2016) Novel RNA-binding activity of MYF5 enhances Ccnd1/Cyclin D1 mRNA translation during myogenesis. Nucleic Acids Res 44:2393-408
Lee, Kwang-Pyo; Shin, Yeo Jin; Panda, Amaresh C et al. (2015) miR-431 promotes differentiation and regeneration of old skeletal muscle by targeting Smad4. Genes Dev 29:1605-17

Showing the most recent 10 out of 28 publications