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Doctoral Thesis
DOI
10.11606/T.42.2010.tde-25032010-145009
Document
Author
Full name
Tavane David Cambiaghi
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2010
Supervisor
Committee
Curi, Rui (President)
Carpinelli, Angelo Rafael
Cury, Yara
Hirata, Mario Hiroyuki
Moriscot, Anselmo Sigari
Title in Portuguese
Estudo do controle traducional de PPAR durante  o processo de diferenciação de macrófagos
Keywords in Portuguese
4E-BP1
Células THP-1
Diferenciação celular
Macrófagos
PPARB
UTR 5\'
Abstract in Portuguese
A diferenciação das células THP-1 em macrófagos, induzida por PMA, é associada ao aumento da expressão de PPAR. A UTR 5` de PPAR regula negativamente sua síntese, porém, o mecanismo molecular envolvido não foi esclarecido. Neste estudo, o estado traducional das células THP-1 diferenciadas por PMA foi investigado em associação à superprodução de PPAR. A presença de uORFs no transcrito de PPAR, contendo códons de iniciação compatíveis com seqüências de Kosak, poderia ser a causa do efeito inibitório da UTR 5`. A incorporação reduzida de L-[U-14C]leucina revelou que a superprodução de PPAR ocorre durante inibição global da tradução, confirmada pela redução dos polissomos. Além disso, desfosforilação de 4E-BP1 foi observada após tratamento com PMA e é associada a inibição da iniciação da tradução e estimulação da tradução dependente de IRES. De fato, a estrutura da UTR 5` de PPAR apresenta características de transcritos que formam IRES. Assim, a produção de PPAR pode ser regulada por IRES e ocorre concomitantemente com a inibição da tradução dependente de cap
Title in English
Translation control of PPAR during macrophage differentiation
Keywords in English
4E-BP1
5\' UTR
Cell differentiation
Macrophages
PPARB
THP-1 cells
Abstract in English
The differentiation of THP-1 cells in macrophages, induced by PMA, is associated to overexpression of PPARb. Previous studies have shown that the PPARb 5' UTR negatively regulates its expression. In our study the translational status of PMA-differentiated THP-1 cells was investigated in association to PPARb overexpression. Putative compatible Kosak initiation codons were identified in the PPARb uORFs and could be involved in the inhibitory effect of 5' UTR. Decreased incorporation of L-[U-14C]leucine in proteins revealed that the overproduction of PPARb in PMA-differentiated THP-1 cells coincides with a global decrease in the protein synthesis process. Translation impairment was confirmed by polysome profile assay. An intense dephosphorylation of 4E-BP by PMA treatment was observed. Dephosphorylated 4E-BP causes inhibition of eIF4E cap-dependent translation initiation and favors IRES-dependent translation. The PPARb 5' UTR structure has some characteristics that resemble the one described for IRES. Therefore, the PPARb production may be controlled by IRES
 
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Publishing Date
2010-03-29
 
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