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Lin, HK, Bergmann, S and Pandolfi, PP (2004) Cytoplasmic PML function in TGF-beta signalling. Nature 431:205-11
Transforming growth factor beta (TGF-beta) is a pluripotent cytokine that controls key tumour suppressive functions, but cancer cells are often unresponsive to it. The promyelocytic leukaemia (PML) tumour suppressor of acute promyelocytic leukaemia (APL) accumulates in the PML nuclear body, but cytoplasmic PML isoforms of unknown function have also been described. Here we show that cytoplasmic Pml is an essential modulator of TGF-beta signalling. Pml-null primary cells are resistant to TGF-beta-dependent growth arrest, induction of cellular senescence and apoptosis. These cells also have impaired phosphorylation and nuclear translocation of the TGF-beta signalling proteins Smad2 and Smad3, as well as impaired induction of TGF-beta target genes. Expression of cytoplasmic Pml is induced by TGF-beta. Furthermore, cytoplasmic PML physically interacts with Smad2/3 and SARA (Smad anchor for receptor activation) and is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-beta receptor in the early endosome. The PML-RARalpha oncoprotein of APL can antagonize cytoplasmic PML function and APL cells have defects in TGF-beta signalling similar to those observed in Pml-null cells. Our findings identify cytoplasmic PML as a critical TGF-beta regulator, and further implicate deregulated TGF-beta signalling in cancer pathogenesis.
Animals; Apoptosis/drug effects; B-Lymphocytes/cytology; B-Lymphocytes/drug effects; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Aging/drug effects; Cell Division/drug effects; Cell Line; Cell Line, Tumor; Cytoplasm/drug effects; Cytoplasm/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Endosomes/drug effects; Endosomes/metabolism; Fibroblasts; Humans; Leukemia, Promyelocytic, Acute/metabolism; Leukemia, Promyelocytic, Acute/pathology; Mice; Mutation/genetics; Neoplasm Proteins/deficiency; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Nuclear Proteins/deficiency; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Oncogene Proteins, Fusion/metabolism; Protein Binding; Protein Transport; Receptors, Transforming Growth Factor beta/metabolism; Signal Transduction/drug effects; Smad2 Protein; Smad3 Protein; Trans-Activators/genetics; Trans-Activators/metabolism; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic/drug effects; Transforming Growth Factor beta/pharmacology; Tumor Suppressor Proteins
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