Abstract
The promyelocytic leukemia tumor suppressor gene (PML) critically regulates several cellular functions that oppose tumorigenesis such as oncogene-induced senescence, apoptosis, the response to DNA damage and to viral infections. PML deficiency occurs commonly in a broad spectrum of human cancers through mechanisms that involve its aberrant ubiquitination and degradation. Furthermore, several viruses encode viral proteins that promote viral replication through degradation of PML. These observations suggest that restoration of PML should lead to potent antitumor effects or antiviral responses. In this review we will summarize the mechanisms involved in PML degradation with the intent to highlight novel therapeutic strategies to trigger PML restoration.
Highlights
The promyelocytic leukemia tumor suppressor gene (PML) was initially identified as a component of the PML-Retinoic Acid Receptor Alpha (RARA) oncoprotein as a result of the chromosomal translocation t (15;17) of acute promyelocytic leukemia (APL) (de The et al, 1990; Goddard et al, 1991; Kakizuka et al, 1991; Pandolfi et al, 1991).The human PML gene is located on chromosome 15, and consists of nine exons that generate several alternative spliced transcripts
Promyelocytic leukemia tumor suppressor gene concentrates in distinct subnuclear structures known as PML-Nuclear Bodies (PML-NB), called PML Oncogenic Domains (POD), Nuclear Domain 10 (ND10), or Kremer bodies (Bernardi and Pandolfi, 2007)
With unpublished experiments we discovered that in the presence of arsenic trioxide (ATO) PIAS1 SUMOylates sites in the PML moiety other than K160, but whether or not these residues have a biological role in determining the response to ATO treatment is not yet known
Summary
Division of Hematology and Oncology, Department of Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. Reviewed by: Hui-Kuan Lin, The University of Texas MD Anderson Cancer Center, USA Valerio Donato, New York University Medical Center, USA. PML deficiency occurs commonly in a broad spectrum of human cancers through mechanisms that involve its aberrant ubiquitination and degradation. Several viruses encode viral proteins that promote viral replication through degradation of PML. These observations suggest that restoration of PML should lead to potent antitumor effects or antiviral responses. In this review we will summarize the mechanisms involved in PML degradation with the intent to highlight novel therapeutic strategies to trigger PML restoration
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