Promyelocytic Leukemia Protein (PML) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis

doi:10.1084/jem.191.4.631

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© The Rockefeller University Press, 0022-1007/2000/2/631/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 4, February 21, 2000 631-640

Original Article

Promyelocytic Leukemia Protein (PML) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis

Sue Zhong^a, Paolo Salomoni^a, Simona Ronchetti^a, Ailan Guo^a, Davide Ruggero^a, and Pier Paolo Pandolfi^a
^a From the Department of Human Genetics and the Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, New York 10021

Correspondence to: Pier Paolo Pandolfi, Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Tel:212-639-6168 Fax:212-717-3374 E-mail:p-pandolfi{at}ski.mskcc.org.

The promyelocytic leukemia protein (PML) gene of acute promyelocyticleukemia (APL) encodes a cell growth and tumor suppressor essentialfor multiple apoptotic signals. Daxx was identified as a moleculeimportant for the cytoplasmic transduction of the Fas proapoptoticstimulus. Here, we show that upon mitogenic activation of maturesplenic lymphocytes, Daxx is dramatically upregulated and accumulatesin the PML nuclear body (NB) where PML and Daxx physically interact.In the absence of PML, Daxx acquires a dispersed nuclear pattern,and activation-induced cell death of splenocytes is profoundlyimpaired. PML inactivation results in the complete abrogationof the Daxx proapoptotic ability. In APL cells, Daxx is delocalizedfrom the NB. Upon retinoic acid treatment, which induces diseaseremission in APL, Daxx relocalizes to the PML NBs. These resultsindicate that PML and Daxx cooperate in a novel NB-dependentpathway for apoptosis and shed new light in the role of PMLin tumor suppression.

Key Words: apoptosis, PML, Daxx, nuclear body, acute promyelocytic leukemia

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