Regulatory mechanisms of c-Myc and their role in Acute Myeloid Leukemia
The c-Myc transcription factor is a key player in cell homeostasis, being commonly deregulated in human carcinogenesis. In this PhD thesis we have addressed the question how regulatory mechanisms restrain the oncogenic activity of c-Myc and its impact on cell differentiation. In the first half, we r...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2010 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/31972 |
| Acceso en línea: | http://hdl.handle.net/10803/31972 |
| Access Level: | acceso abierto |
| Palabra clave: | c-Myc Retinoic acid receptor alpha (RARα) Vitamin D p21-activated kinase 2 (Pak2) PML-RARα Retinoic acid Transducció de senyal Regulació gènica Diferenciació cel·lular Leucèmia Càncer 616.4 |
| Sumario: | The c-Myc transcription factor is a key player in cell homeostasis, being commonly deregulated in human carcinogenesis. In this PhD thesis we have addressed the question how regulatory mechanisms restrain the oncogenic activity of c-Myc and its impact on cell differentiation. In the first half, we report that PML promotes destabilization of c-Myc protein and re-activation of c-Myc-repressed target genes. The consequent re-expression of the cell cycle inhibitor CDKN1A/p21 mediates differentiation of leukemic cells. In the second half of the thesis we identified a novel mechanism of gene regulation by c-Myc, which is mediated through its interaction with DNA-bound RARα. In undifferentiated cells, c-Myc/Max dimers cooperate with RARα in the repression of genes required for differentiation. Upon phosphorylation of c-Myc by the previously identified Pak2, the complex switches from a repressive to an activating function by releasing Max and recruiting transcriptional coactivators. These findings add a new and at least partially Max-independent mechanism for transcriptional regulation by c-Myc and also discover an unexpected function of c-Myc in inhibiting and promoting cellular differentiation. Taken together, our results describe two new mechanisms that counteract the oncogenic activity of c-Myc. Both PML and Pak2 can be considered as tumor suppressors since they modulate c-Myc function in a way that ultimately promotes differentiation of leukemic cells. This knowledge provides the basis for novel approaches to be exploited for the development of c-Myc-targeted therapies. |
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