| Research Abstract |
The AML1 gene is the most frequent target of chromosome translocations and other mutations in acute myeloid leukemia. We purified AML1 complex and found that the complex contained p300/CBP, MOZ, PML, and HIPK2 as well as CBFb. PML is a nuclear protein that functions as a regulator of transcription, cell proliferation, apoptosis, and myeloid cell differentiation. PML interacts with several transcription factors, such as AML1, PU.1, C/EBP and p53, as well as their co-activators, such as HIPK2 and p300, resulting in the activation of transcription. Although PML is thought to achieve transcription activation by stabilizing the transcription-factor complex, little is known about the underlying molecular mechanism. To clarify the role of PML in transcription regulation, PML complex was purified and Fbx3, Skp1, and Cullin1 were identified as novel components of this complex. Fbx3 formed SCFFbx3 ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. PML inhibited this degradation through a mechanism that unexpectedly did not involve inhibition of the ubiquitination of HIPK2. PML, Fbx3, and HIPK2 synergistically activated p53-induced transcription. Our findings suggest that PML stabilizes the transcription-factor complex by protecting HIPK2 and p300 from SCFFbx3-induced degradation until transcription is completed. In contrast, the leukemia-associated fusion PML-RAR α induced the degradation of HIPK2, suggesting that PML-RAR α degrade co-activators to block transcription by antagonizing PML.
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