Promyelocytic leukemia protein is required for gain of function by mutant p53.
Mutations in the p53 tumor suppressor are the most common genetic events in human cancer. These mutations not only result in a loss of wild-type p53 activity, but can also lead to a gain of new oncogenic properties. Understanding how these gained functions are regulated is in its infancy. In this study, we show that the promyelocytic leukemia (PML) protein is an important regulator of mutant p53. We show that PML interacts with mutant p53. Importantly, PML enhances the transcriptional activity of mutant p53. Unexpectedly, PML is required for the proliferation and colony formation of cancer cells bearing mutant p53. Down-regulation of PML expression inhibits the growth of mutant p53-expressing cancer cells, predominantly by promoting cell cycle arrest. Our results suggest that the tumor suppression function of PML depends on the status of p53. In the context of mutant p53, PML enhances its cancer-promoting activities.
Haupt
Sue
S
Research Division, The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sue.Haupt@petermac.org
di Agostino
Silvia
S
Mizrahi
Inbal
I
Alsheich-Bartok
Osnat
O
Voorhoeve
Mathijs
M
Damalas
Alex
A
Blandino
Giovanni
G
Haupt
Ygal
Y
D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D055785:Gene Knockdown Techniques; D005799:Genes, Dominant / Q000235:genetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D050505:Mutant Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human