Function of PML nuclear bodies (PML-NBs)
The nucleus of a mammalian cell is organized in multiple nuclear domains, which include the heterogeneous family of nuclear bodies (NBs). Promyelocytic leukemia nuclear bodies (PML-NBs), one specific class of NBs, appear as distinct spherical structures in the cell nucleus and are found in virtually all mammalian cells. PML-NBs form multi-protein complexes and their number, size and protein composition dramatically changes in response to DNA damage, oncogenic transformation and viral infection.
Various tumor suppressor proteins, including p53, CBP as well as the potential tumor suppressor HIPK2, are functionally regulated through PML-NB recruitment.
Although it is established that PML-NBs and their components play an important role in multiple apoptosis pathways, including those controlled by p53 and death receptor CD95 (Fas/APO-1), the molecular mechanisms by which PML-NBs regulate DNA damage response and apoptosis signaling remain largely unclear.
Recently, we identified the FLASH protein, a known mediator of death receptor-induced apoptosis as a new PML-NB component. Remarkably, after activation of the death receptor CD95 FLASH translocates from PML-NBs into the cytoplasm were it associates with caspase-8 at the mitochondria, resulting in apoptosis induction. Our findings elucidated an unforeseen signaling pathway that links CD95 signaling to the nucleus and nuclear bodies (Milovic-Holm et al. EMBO J. 2007).
For selective reading:
Krieghoff-Henning & Hofmann (2008). BBA Molecular Cell Research.
Milovic-Holm et al. (2007), EMBO Journal.
Fleischer et al. (2006), Exp.Cell.Res.
Herzer et al. (2005), Cancer Research.
Hofmann & Will (2003). Cell Death & Differentiation.
Hofmann et al. (2002), Nature Cell Biology.
