The role of the rpl5/rpl11/5s rrna complex in mediating p53 levels in response to c-myc depletion in colorectal carcinoma
- Autores: Carmen Morecelle Magaña
- Directores de la Tesis: George Thomas (dir. tes.), Albert Tauler Girona (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Laura Soucek (presid.), José Luis Rosa López (secret.), Raúl Méndez de la Iglesia (voc.)
- Materias:
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- Resumen
In most human cancers, the c-Myc transcription factor is deregulated and/or its levels are elevated, particularly in colorectal cancer (CRC). Earlier studies suggested a direct relationship between ribosome biogenesis and the c-Myc induced tumorigenesis, with recent reports arguing that ribosomal proteins L5 (RPL5) and RPL11 act against c-Myc as tumor suppressors by inhibiting MDM2 and inducing p53 stabilization. Our laboratory recently showed that upon inhibition of ribosome biogenesis, a nascent pre-ribosomal complex containing RPL5, RPL11 and 5S rRNA is redirected from 60S ribosome biogenesis to the inhibition of MDM2 and p53 stabilization. We have termed this response the impaired ribosome biogenesis checkpoint (IRBC). Here, we demonstrate that c-Myc silencing causes a drop in p53 protein levels through increased proteasome degradation. Moreover, c-Myc depletion significantly reduces the levels of the RPL5/RPL11/5S rRNA complex, even following impaired ribosome biogenesis by treatment with Actinomycin D, a Polymerase I inhibitor. Thus, diminished p53 stability appears to be mediated by a reduction of the RPL5/RPL11/5S rRNA complex and the inhibition of MDM2. This thesis examines the relationship between c-Myc, p53 and components of the IRBC complex, including the 5S rRNA, defining a mechanism by which cells respond to c-Myc levels.
