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Mol Cell Biol, February 1998, p. 1084-1093, Vol. 18, No. 2
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Promyelocytic Leukemia Gene Product (PML) Forms Stable Complexes with the Retinoblastoma Protein

Myriam Alcalay,1,* Lucia Tomassoni,1 Emanuela Colombo,1 Stephan Stoldt,1 Francesco Grignani,2 Marta Fagioli,2 Laszlo Szekely,3 Kristian Helin,1 and Pier Giuseppe Pelicci1,2

Department of Experimental Oncology, European Institute of Oncology, 20141 Milan,1 and Istituto di Medicina Interna e Scienze Oncologiche, Università degli Studi di Perugia, Policlinico Monteluce, 06100 Perugia,2 Italy, and Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden3

Received 27 May 1997/Returned for modification 27 July 1997/Accepted 24 October 1997

PML is a nuclear protein with growth-suppressive properties originally identified in the context of the PML-retinoic acid receptor alpha  (RARalpha ) fusion protein of acute promyelocytic leukemia. PML localizes within distinct nuclear structures, called nuclear bodies, which are disrupted by the expression of PML-RARalpha . We report that PML colocalizes with the nonphosphorylated fraction of the retinoblastoma protein (pRB) within nuclear bodies and that pRB is delocalized by PML-RARalpha expression. Both PML and PML-RARalpha form complexes with the nonphosphorylated form of pRB in vivo, and they interact with the pocket region of pRB. The regions of PML and PML-RARalpha involved in pRB binding differ; in fact, the B boxes and the C-terminal region of PML, the latter of which is not present in PML-RARalpha , are essential for the formation of stable complexes with pRB. Functionally, PML abolishes activation of glucocorticoid receptor-regulated transcription by pRB, whereas PML-RARalpha further increases it. Our results suggest that PML may be part of transcription-regulatory complexes and that the oncogenic potential of the PML-RARalpha protein may derive from the alteration of PML-regulated transcription.

* Corresponding author. Mailing address: Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy. Phone: (39)-2-57489825. Fax: (39)-2-57489851. E-mail: malcalay{at}ieo.cilea.it.




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