Functions and dys-functions of promyelocytic leukemia protein PML
- 12 Downloads
The promyelocytic leukemia protein PML has been previously recognized as a critical and essential regulator of a broad number of cellular functions. At nuclear level PML forms the PML-nuclear bodies, where it can sequester and influence the post-translational modification of a wide number of proteins, ultimately affecting their regulative role in DNA transcription. In such a way, PML acts as a key player in strategic cellular activities like as the antiviral defense, in the regulation of the cell cycle, in senescence and programmed cell death. In addition, PML can redistribute also at cytoplasmic level, where it associates to the endoplasmic reticulum or is recruited to mitochondrial-associated membranes. Here it can interact with key cellular proteins like as p53 and influence cell metabolism, mitochondrial calcium upload and autophagy. Altogether, all these findings depict PML as a protein able to exert a widespread action mainly focused on pro-apoptotic and cytostatic activities. Anyway, presence of “Janus-like” pro-tumoral behaviors have been reported, prompting for further investigation to better dissect and highlight all the possible roles that PML can assume in the different physiological or pathological environments. In this review, we discuss the role of PML in multiple cellular functions and pathologic scenarios and summarize the players that control PML protein both at nuclear and at cytoplasmic level.
KeywordsPML functions Antiviral response Senescence Cell death Metabolism Cancer
Fundings were provided by local funds from the University of Ferrara, the Italian Association for Cancer Research (AIRC: IG-19803), the Italian Ministry of Health, and by a Fondazione Cariplo grant.
- Buczek ME, Miles AK, Green W, Johnson C, Boocock DJ, Pockley AG, Rees RC, Hulman G, van Schalkwyk G, Parkinson R, Hulman J, Powe DG, Regad T (2016) Cytoplasmic PML promotes TGF-beta-associated epithelial-mesenchymal transition and invasion in prostate cancer. Oncogene 35(26):3465–3475CrossRefGoogle Scholar
- Carracedo A, Weiss D, Leliaert AK, Bhasin M, de Boer VC, Laurent G, Adams AC, Sundvall M, Song SJ, Ito K, Finley LS, Egia A, Libermann T, Gerhart-Hines Z, Puigserver P, Haigis MC, Maratos-Flier E, Richardson AL, Schafer ZT, Pandolfi PP (2012) A metabolic prosurvival role for PML in breast cancer. J Clin Invest 122(9):3088–3100CrossRefGoogle Scholar
- Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ (1997) Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences. Blood 89(2):376–387Google Scholar
- Koken MH, Puvion-Dutilleul F, Guillemin MC, Viron A, Linares-Cruz G, Stuurman N, de Jong L, Szostecki C, Calvo F, Chomienne C et al (1994) The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO J 13(5):1073–1083Google Scholar
- Kuchay S, Giorgi C, Simoneschi D, Pagan J, Missiroli S, Saraf A, Florens L, Washburn MP, Collazo-Lorduy A, Castillo-Martin M, Cordon-Cardo C, Sebti SM, Pinton P, Pagano M (2017) PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth. Nature 546(7659):554–558Google Scholar
- Marchi S, Bittremieux M, Missiroli S, Morganti C, Patergnani S, Sbano L, Rimessi A, Kerkhofs M, Parys JB, Bultynck G, Giorgi C, Pinton P (2017) Endoplasmic reticulum-mitochondria communication through Ca(2+) signaling: the importance of mitochondria-associated membranes (MAMs). Adv Exp Med Biol 997:49–67CrossRefGoogle Scholar
- Missiroli S, Bonora M, Patergnani S, Poletti F, Perrone M, Gafa R, Magri E, Raimondi A, Lanza G, Tacchetti C, Kroemer G, Pandolfi PP, Pinton P, Giorgi C (2016) PML at mitochondria-associated membranes is critical for the repression of autophagy and cancer development. Cell Rep 16(9):2415–2427CrossRefGoogle Scholar
- Zhou W, Cheng L, Shi Y, Ke SQ, Huang Z, Fang X, Chu CW, Xie Q, Bian XW, Rich JN, Bao S (2015) Arsenic trioxide disrupts glioma stem cells via promoting PML degradation to inhibit tumor growth. Oncotarget 6(35):37300–37315Google Scholar