Role of c-Myc in gene regulation and cellular differentiation

The deregulation of transcription factors, concomitantly with epigenetic alterations, is a hallmark of many types of cancer. Over-expression of Myc suffices for mitogen-independent proliferation and blocks terminal differentiation. Numerous studies have further shown that Myc activation was sufficient to provoke diverse type of cancers and that Myc is continuously required for maintaining the transformed phenotype. Our initial results suggested that the promyelocytic leukemia protein (PML) physically interacts with c-Myc and that this binding capacity is retained in the context of the oncogenic fusion protein PML-RARa.

We thus hypothesized that PML plays an important role in controlling Myc stability and in turn Myc-dependent transcription. The interaction of PML with Myc does not only result in a reduction of its protein levels but also in an inhibition of its function as transcriptional repressor. Consequently, PML induces the re-activation of genes that inhibit cell cycle and promote differentiation such as p21. This explains how PML synergizes with Vitamin D in the induction of granulocytic differentiation of U937 cells.

We are now further exploring these initial findings and investigating the cross-talk between Myc and the retinoic acid pathway.

Selected publications from our group on this research line:

• Buschbeck M., Uribesalgo I., Ledl A., Gutierrez A., Minucci S., Muller S., and Di Croce L. (2007) PML4 induces differentiation by Myc destabilization. Oncogene, 26, 3415-3422.
• Brenner C., Deplus R., Didelot C., Loriot A., Vire E., De Smet C., Gutierrez A., Danovi D., Bernard D., Boon T., Pelicci PG., Amati B., Kouzarides T., de Launoit Y., Di Croce L., Fuks F. (2005) Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J. 24, 336-346.