Cytoplasmic function of APL-associated PML mutants

On Thursday November 17th, 2005 at 5:15 pm, Dr. Paolo Salomoni will be our guest HPI-seminar speaker. Dr.Salomoni, currently head of a research group at the MRC Toxicology Unit in Leicester is a top scientist in the research field "PML proteins and their functions in cell physiology as well as in leukemia. In order to attract your attention, a brief introduction into this research area and a glimpse on the latest breakthrough results Dr. Salomoni will present is given below.

The PML tumour suppressor of APL regulates major apoptotic and growth suppressive pathways. In APL, PML is involved in the t15;17 chromosomal translocation generating the PML-RARα fusion protein. PML-RARα is the oncogene of APL and inhibits both RARα and PML cellular functions. PML functional inactivation results in a marked survival and proliferative advantage. In contrast, impairment of RARα function causes a block of differentiation at the promyelocytic stage. Treatment with pharmacological doses of retinoic acid (RA) causes the release of the differentiation block and remission in APL patients. Nevertheless, remission is often followed by relapse events. Two missense mutations in the remaining PML allele have been identified in relapsed APL patients, which give rise to truncated cytoplasmic PML proteins (Mut PML). APL patients carrying these mutations display resistance to retinoic acid and very poor prognosis. Here we show that Mut PML associates with cytoplasmic regions we refer to as PML-cytoplasmic bodies (PML-CBs). We also show that Mut PML inhibits p53 function. Moreover, Mut PML interacts with PML-RARα in the cytoplasm and induces its stabilization upon retinoic acid (RA) treatment, thus potentiating PML-RARα-mediated inhibition of RA-dependent transcription. Remarkably, a mutant form of PML-RARα that accumulates in the cytoplasm causes the redistribution of RXRα to PML-CBs and inhibits RA-dependent transcription. Furthermore, we show that the bcr3 PML-RARα form is to a high degree cytoplasmic and a more potent inhibitor of RA-dependent transcription. Taken together, these findings reveal novel insights into the molecular mechanisms contributing to APL.

For additional information on Dr. Salomini research work on this subject please refer to the following selected publications from the references provided:

• Zhong S, Salomoni P (co-first author), Ronchetti S, Guo A, Ruggero D, Pandolfi P Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J Exp Med 2000 191:631-40.
• Zhong S, Salomoni P, Pandolfi PP. The transcriptional role of PML and the nuclear body. Nat Cell Biol 2000 2:E85-90.
• Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W, Paolo Pandolfi P. The function of PML in p53-dependent apoptosis. Nat Cell Biol 2000 2:730-6.
• Salomoni P, Pandolfi PP. The role of PML in tumor suppression. Cell 2002 108:165-70.
• Salomoni P, Bernardi R, Bergmann S, Changou A, Tuttle S, Pandolfi PP. The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood. 2004 Dec 30 (AOP).
• Bernassola F, Salomoni P, Oberst A, Di Como CJ, Pagano M, Melino G, Pandolfi PP. Ubiquitin-dependent degradation of p73 is inhibited by PML. J Exp Med 2004 199:1545-57.
• Khelifi AF, Stagno D'Alcontres M, Salomoni P. Daxx is required for stress-induced cell death and JNK activation. Cell Death Differ 2005 Apr 29 (AOP).
• Salomoni P, Guernah I, Pandolfi PP. The PML nuclear body associated protein Daxx regulates the cellular response to CD40. Cell Death Differ 2005, in press.
• Salomoni P, Khelifi AF. Daxx: death or survival protein? Trends Cell Biol 2006, in press.