Role of PML and the PML-nuclear body in the control of programmed cell death.
PML is a tumor suppressor implicated in leukemia and cancer pathogenesis. PML epitomizes a multiprotein nuclear structure, the PML-nuclear body (PML-NB), whose proper formation and function depends on PML. Studies in knockout (KO) mice and cells unraveled an essential pleiotropic role for PML in multiple p53-dependent and -independent apoptotic pathways. As a result, Pml(-/-) mice and cells are protected from apoptosis triggered by a number of stimuli such as ionizing radiation, interferon, ceramide, Fas and TNF. It is becoming apparent that PML and the PML-NB act as molecular hubs for the induction and/or reinforcement of programmed cell death through a selective and dynamic regulation of proapoptotic transcriptional events. In addition, recent observations propose a role for PML in checkpoint responses upon DNA damage. Moreover, PML and the PML-NB have also been implicated in the control of genomic stability and DNA repair. Here, we will discuss the molecular mechanisms by which PML regulates these processes and the implication of these findings for cancer pathogenesis and therapy.
Bernardi
Rosa
R
Molecular Biology Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, 1275 York Avenue, New York, NY 10021, USA.
Pandolfi
Pier Paolo
PP
D000818:Animals; D017209:Apoptosis; D043171:Chromosomal Instability; D004260:DNA Repair; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009369:Neoplasms / Q000209:etiology; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human