Promyelocytic leukemia protein

1BOR, 2MVW, 2MWX, 4WJN, 4WJO537118854ENSG00000140464ENSMUSG00000036986P29590Q60953NM_033244NM_033246NM_033247NM_033249NM_008884NM_178087NM_001311088NP_150249NP_150250NP_150252NP_150253NP_001298017NP_032910NP_835188Promyelocytic leukemia protein (PML) (also known as MYL, RNF71, PP8675 or TRIM19) is the protein product of the PML gene. PML protein is a tumor suppressor protein required for the assembly of a number of nuclear structures, called PML-nuclear bodies, which form amongst the chromatin of the cell nucleus. These nuclear bodies are present in mammalian nuclei, at about 1 to 30 per cell nucleus. PML-NBs are known to have a number of regulatory cellular functions, including involvement in programmed cell death, genome stability, antiviral effects and controlling cell division. PML mutation or loss, and the subsequent dysregulation of these processes, has been implicated in a variety of cancers.1bor: TRANSCRIPTION FACTOR PML, A PROTO-ONCOPROTEIN, NMR, 1 REPRESENTATIVE STRUCTURE AT PH 7.5, 30 C, IN THE PRESENCE OF ZINC Promyelocytic leukemia protein (PML) (also known as MYL, RNF71, PP8675 or TRIM19) is the protein product of the PML gene. PML protein is a tumor suppressor protein required for the assembly of a number of nuclear structures, called PML-nuclear bodies, which form amongst the chromatin of the cell nucleus. These nuclear bodies are present in mammalian nuclei, at about 1 to 30 per cell nucleus. PML-NBs are known to have a number of regulatory cellular functions, including involvement in programmed cell death, genome stability, antiviral effects and controlling cell division. PML mutation or loss, and the subsequent dysregulation of these processes, has been implicated in a variety of cancers. PML was poorly understood until described in the findings of Grignani et al in their 1996 study of patients with acute promylocytic leukemia (APL). It was found that the karyotype of 90% of APL patients included a reciprocal translocation, resulting in the fusion of the Retinoic Acid Receptor (RARalpha) gene of chromosome 17 and the PML gene of chromosome 15, which had not previously been characterized. The resultant PML/RARalpha oncofusion gene was shown to disturb normal PML and RARalpha function, thus inhibiting the terminal differentiation of blood precursor cells and allowing the maintenance of a reserve of undifferentiated cells for cancerous progression. This implication of the PML gene in a pathological context led to a greater focus on the gene in future years. The PML gene is roughly 53 kilobase pairs in length and is located on the q arm of chromosome 15. It consists of 10 exons that are subject to shuffling through alternative splicing, yielding more than 15 known PML protein isoforms. While the isoforms vary at their c-terminal domain, they all contain a TRIpartite motif encoded by the first three exons of the gene. The TRIpartite motif consists of a zinc RING finger, two zinc binding domains, termed the B1 and B2 boxes, and an RBCC dimerization domain composed of two alpha helical coiled coil domains. The PML gene is under control at the transcriptional, translational and post translational control. The promoter region of the gene contains targets of Signal Transducer and Activator of Transcription (STATs), interferon regulatory factors, and p53 protein, indicating the intricacy of its involvement in cellular functions. In addition to regulation through alternative splicing, the protein product is subject to post-translational modifications such as acetylation and phosphorylation. The c-terminus contains serine residues that are phosphorylated by casein kinases, and there are several tyrosine and threonine residues which can also be phosphorylation targets. PML phosphorylation triggers further modification through the attachment of SUMO proteins to the RING domain by UBC9 SUMO-conjugating enzyme, which occurs in a cell cycle dependent way. PML contains a SUMO-binding domain necessary for its interaction with other SUMOylated proteins such as itself and many others. Both ubiquitination and SUMOylation of PML protein can trigger its degradation in the proteasome, thus providing a means of modulating PML protein lability within the cell. PML is translated in the cytoplasm of the cell, but its N-terminus contains a nuclear localization signal which causes its import to the nucleus. Within the nucleus, sumoylated PML proteins multimerize with one another through interactions at the RBCC domain.This forms a ring-like structure that binds to the nuclear matrix, forming a PML-Nuclear body (PML-NB). The edge of the ring-like protein mutimer features protein threads that extend out from the ring and make contact with chromatin fibers. This maintains the position of the PML-NBs within the nucleus, as well as the stability of the protein. When the chromatin is stressed, such as during apoptosis, the PML-NB becomes unstable and the PML bodies are redistributed into microstructures. These microstructures contain PML protein but not the many interacting proteins normally associated with PML-NBs. PML-NBs are not randomly distributed throughout the nucleus, but are found within the nucleus and are commonly associated with other nuclear bodies such as splicing speckles and nucleoi, as well as regions that are rich in genes and are actively being transcribed . Particularly, PML-NB have been shown to associate with genes such as the MHC I cluster of genes, as well as the p53 gene. The exact significance of this association is unclear, however evidence suggests that PML-NBs may influence transcription at these specific gene sites. The PML-NBs have a wide array of functions, and a large role in cell regulation. They exert their wide range of actions through interactions with varying proteins localized to the PML-NBs. It is thought that the specific biochemical function performed by PML-NBs may be serving as an E3 ligase for the sumoylation of other proteins. The true function, however, remains unclear, and several possible models have been proposed for PML-NB function, including nuclear storage of proteins, serving as a dock where other proteins accumulate to be post-translationally modified, direct involvement with transcription, and chromatin regulation. PML-NBs also play a role in transcriptional regulation. PML-NBs have been shown to increase the transcription of some genes, while repressing the transcription of other genes. It has been suggested that the mechanism by which PML-NBs do this is via a chromatin-remodelling processes, although this is uncertain.