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Post-translational modifications of PML: consequences and implications.

Cheng X, Kao HY - Front Oncol (2013)

Bottom Line: The tumor suppressor promyelocytic leukemia protein (PML) predominantly resides in a structurally distinct sub-nuclear domain called PML nuclear bodies.Post-translational modifications, such as SUMOylation, phosphorylation, acetylation, and ubiquitination of PML add a complex layer of regulation to the physiological function of PML.In this review, we discuss the fast-moving horizon of post-translational modifications targeting PML.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University Cleveland, OH, USA ; Comprehensive Cancer Center, Case Western Reserve University Cleveland, OH, USA ; University Hospital of Cleveland, Case Western Reserve University Cleveland, OH, USA.

ABSTRACT
The tumor suppressor promyelocytic leukemia protein (PML) predominantly resides in a structurally distinct sub-nuclear domain called PML nuclear bodies. Emerging evidences indicated that PML actively participates in many aspects of cellular processes, but the molecular mechanisms underlying PML regulation in response to stress and environmental cues are not complete. Post-translational modifications, such as SUMOylation, phosphorylation, acetylation, and ubiquitination of PML add a complex layer of regulation to the physiological function of PML. In this review, we discuss the fast-moving horizon of post-translational modifications targeting PML.

No MeSH data available.


Related in: MedlinePlus

Phylogenetic tree of PML proteins in mammals. The phylogenetic tree was generated using the maximum likelihood method with amino acid substitutions in the Jones–Taylor–Thornton model at a uniform rate. The bootstrap score is labeled at the branches.
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Figure 1: Phylogenetic tree of PML proteins in mammals. The phylogenetic tree was generated using the maximum likelihood method with amino acid substitutions in the Jones–Taylor–Thornton model at a uniform rate. The bootstrap score is labeled at the branches.

Mentions: Promyelocytic leukemia protein (PML) is a tumor suppressor that was initially identified as a fusion partner of human retinoic acid receptor alpha (RARα) as a result of a chromosomal translocation found in the acute promyelocytic leukemia patients (APL; de Thé et al., 1991; Kakizuka et al., 1991). PML is expressed and conserved in all mammals (Figure 1). It is enriched in proteinaceous masses called PML nuclear bodies (NBs), which are visualized as spherical nuclear speckles (Ascoli and Maul, 1991; Daniel et al., 1993). Many proteins have been identified as PML interacting partners or components of the PML NBs. PML NBs are implicated in various cellular activities, including transcriptional regulation, cell cycle control, post-translational modification, anti-viral response, DNA damage response and repair, apoptosis, and metabolism (Kitamura et al., 2005; Van Damme et al., 2010; Kim et al., 2011; Carracedo et al., 2012; Cheng and Kao, 2012; Ito et al., 2012). There are nine experimentally verified isoforms in human according to the NCBI database (Figure 2), all of which have the N-terminal 418 amino acids in common. A nomenclature system of PML isoforms using roman numerals was proposed by Jensen et al. (2001). Although widely used by researchers, this nomenclature system, however, has not converged with the references used in common sequence databases of NCBI or Ensembl. Sometimes, ambiguous references were presented in the literature. In this review, we will refer to the PML isoforms using the names currently implemented by the NCBI database and annotate each isoform with names from other nomenclature systems (Figure 2). There is only limited information available on the function of most of the isoforms; although a growing body of evidence suggests that different isoforms may have specific functions. For example, PML isoform 2 is implicated in scaffolding PML NBs (Weidtkamp-Peters et al., 2008), while PML isoforms 1 and 9 are involved in the antiviral activity (Cuchet et al., 2011). PML isoform 6, the best-studied isoform, interacts and recruits p53 to PML NBs (Fogal et al., 2000). Unless otherwise specified, this review will summarize our understanding of the post-translational modifications using PML isoform 6 as a reference and focus on SUMOylation, phosphorylation, ubiquitination, and the newly identified acetylation. These modifications regulate the ability of PML to interact with various partners and confer stress- and signal-dependent regulation of PML or its binding proteins.


Post-translational modifications of PML: consequences and implications.

Cheng X, Kao HY - Front Oncol (2013)

Phylogenetic tree of PML proteins in mammals. The phylogenetic tree was generated using the maximum likelihood method with amino acid substitutions in the Jones–Taylor–Thornton model at a uniform rate. The bootstrap score is labeled at the branches.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539660&req=5

Figure 1: Phylogenetic tree of PML proteins in mammals. The phylogenetic tree was generated using the maximum likelihood method with amino acid substitutions in the Jones–Taylor–Thornton model at a uniform rate. The bootstrap score is labeled at the branches.
Mentions: Promyelocytic leukemia protein (PML) is a tumor suppressor that was initially identified as a fusion partner of human retinoic acid receptor alpha (RARα) as a result of a chromosomal translocation found in the acute promyelocytic leukemia patients (APL; de Thé et al., 1991; Kakizuka et al., 1991). PML is expressed and conserved in all mammals (Figure 1). It is enriched in proteinaceous masses called PML nuclear bodies (NBs), which are visualized as spherical nuclear speckles (Ascoli and Maul, 1991; Daniel et al., 1993). Many proteins have been identified as PML interacting partners or components of the PML NBs. PML NBs are implicated in various cellular activities, including transcriptional regulation, cell cycle control, post-translational modification, anti-viral response, DNA damage response and repair, apoptosis, and metabolism (Kitamura et al., 2005; Van Damme et al., 2010; Kim et al., 2011; Carracedo et al., 2012; Cheng and Kao, 2012; Ito et al., 2012). There are nine experimentally verified isoforms in human according to the NCBI database (Figure 2), all of which have the N-terminal 418 amino acids in common. A nomenclature system of PML isoforms using roman numerals was proposed by Jensen et al. (2001). Although widely used by researchers, this nomenclature system, however, has not converged with the references used in common sequence databases of NCBI or Ensembl. Sometimes, ambiguous references were presented in the literature. In this review, we will refer to the PML isoforms using the names currently implemented by the NCBI database and annotate each isoform with names from other nomenclature systems (Figure 2). There is only limited information available on the function of most of the isoforms; although a growing body of evidence suggests that different isoforms may have specific functions. For example, PML isoform 2 is implicated in scaffolding PML NBs (Weidtkamp-Peters et al., 2008), while PML isoforms 1 and 9 are involved in the antiviral activity (Cuchet et al., 2011). PML isoform 6, the best-studied isoform, interacts and recruits p53 to PML NBs (Fogal et al., 2000). Unless otherwise specified, this review will summarize our understanding of the post-translational modifications using PML isoform 6 as a reference and focus on SUMOylation, phosphorylation, ubiquitination, and the newly identified acetylation. These modifications regulate the ability of PML to interact with various partners and confer stress- and signal-dependent regulation of PML or its binding proteins.

Bottom Line: The tumor suppressor promyelocytic leukemia protein (PML) predominantly resides in a structurally distinct sub-nuclear domain called PML nuclear bodies.Post-translational modifications, such as SUMOylation, phosphorylation, acetylation, and ubiquitination of PML add a complex layer of regulation to the physiological function of PML.In this review, we discuss the fast-moving horizon of post-translational modifications targeting PML.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University Cleveland, OH, USA ; Comprehensive Cancer Center, Case Western Reserve University Cleveland, OH, USA ; University Hospital of Cleveland, Case Western Reserve University Cleveland, OH, USA.

ABSTRACT
The tumor suppressor promyelocytic leukemia protein (PML) predominantly resides in a structurally distinct sub-nuclear domain called PML nuclear bodies. Emerging evidences indicated that PML actively participates in many aspects of cellular processes, but the molecular mechanisms underlying PML regulation in response to stress and environmental cues are not complete. Post-translational modifications, such as SUMOylation, phosphorylation, acetylation, and ubiquitination of PML add a complex layer of regulation to the physiological function of PML. In this review, we discuss the fast-moving horizon of post-translational modifications targeting PML.

No MeSH data available.


Related in: MedlinePlus