Characterization of DIP-2-mediated ubiquitination and degradation of the PML tumor suppressor protein
Date Issued
2009
Date
2009
Author(s)
Chiang, Cheng-Ta
Abstract
The promyelocytic leukemia (PML) is a tumor suppressor protein and is critical for the formation PML-nuclear body (PML-NB), a subnuclear macromolecular structure implicated in the regulation of various cellular functions, such as induction of apoptosis, growth suppression and cellular senescence. PML is activated in response to various stress signals and is frequently downregulated in human tumors. However, the factors regulating PML stability have not been completely understood. In this thesis, we identify the BTB-Kelch protein DIP-2 as a negative regulator of PML stability. DIP-2 contains an N-terminal BTB/POZ domain, an internal BACK domain and C-terminal six Kelch repeats. Previous study in our laboratory indicates that DIP-2 associates with Cul3 to form an ubiquitin ligase complex. Here, we show that DIP-2 interacts with PML through its substrate recognition domain. This interaction targets PML to the Cul3-DIP-2 complex for ubiquitination and, consequently, degradation. Unlike PML, DIP-2 is not sumoylated and DIP-2 mediates PML ubiquitination through a PML sumoylation-independent manner. Furthermore, PML sumoylation at K490 does not interfere with its ubiquitination by DIP-2-Cul3. However, DIP-2-mediated PML ubiquitination requires the activity of peptidyl prolyl cis/trans isomerase Pin1, which is known to trigger PML degradation. DIP-2-meditated PML ubiquitination also requires the Ser518/527 residues of PML, both of which are within the Pin1 targeting motif, pS/T-P. Together, this study not only identifies the DIP-2-Cul3 complex as an ubiquitin ligase for PML, but also reveals a novel PML degradation pathway.
Subjects
ubiquitination
sumoylation
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