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Molecular and Cellular Biology, December 2008, p. 7126-7138, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00897-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

PML Activates Transcription by Protecting HIPK2 and p300 from SCFFbx3-Mediated Degradation{triangledown} ,{dagger}

Yutaka Shima,1 Takito Shima,1 Tomoki Chiba,2 Tatsuro Irimura,3 Pier Paolo Pandolfi,4 and Issay Kitabayashi1*

Molecular Oncology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan,1 Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8572, Japan,2 Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan,3 Beth Israel Deaconess Medical Center and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 021154

Received 5 June 2008/ Returned for modification 7 July 2008/ Accepted 12 September 2008

PML, a nuclear protein, interacts with several transcription factors and their coactivators, 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, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 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{alpha} induced the degradation of HIPK2. We discuss the roles of PML and PML-retinoic acid receptor {alpha}, as well as those of HIPK2 and p300 ubiquitination, in transcriptional regulation and leukemogenesis.

* Corresponding author. Mailing address: Molecular Oncology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81 3 3547 5274. Fax: 81 3 3542 0688. E-mail: ikitabay{at}ncc.go.jp

{triangledown} Published ahead of print on 22 September 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2008, p. 7126-7138, Vol. 28, No. 23
0270-7306/08/$08.00+0     doi:10.1128/MCB.00897-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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