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Finding a role for PML in APL pathogenesis: a critical assessment of potential PML activities
1Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York 10029, USA.
Abstract:
In normal mammalian cells the promyelocytic leukemia protein (PML) is primarily localized in multiprotein nuclear complexes called PML nuclear bodies. However, both PML and PML nuclear bodies are disrupted in acute promyelocytic leukemia (APL). The treatment of APL patients with all-trans retinoic acid (ATRA) results in clinical remission associated with blast cell differentiation and reformation of the PML nuclear bodies. These observations imply that the structural integrity of the PML nuclear body is critically important for normal cellular functions. Indeed, PML protein is a negative growth regulator capable of causing growth arrest in the G(1) phase of the cell cycle, transformation suppression, senescence and apoptosis. These PML-mediated, physiological effects can be readily demonstrated. However, a discrete biochemical and molecular model of PML function has yet to be defined. Upon first assessment of the current PML literature there appears to be a seemingly endless list of potential PML partner proteins implicating PML in a variety of regulatory mechanisms at every level of gene expression. The purpose of this review is to simplify this confusing field of research by using strict criteria to deduce which models of PML body function are well supported.
Insights
Promyelocytic leukemia protein (PML) nuclear bodies are crucial for normal cell function and disrupted in acute promyelocytic leukemia (APL). This review clarifies PML
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Promyelocytic leukemia protein (PML) localizes to nuclear bodies in mammalian cells.
- PML and its nuclear bodies are disrupted in acute promyelocytic leukemia (APL).
- All-trans retinoic acid (ATRA) treatment in APL patients restores PML nuclear bodies and induces remission.
Purpose of the Study:
- To review and simplify the complex field of PML protein function.
- To identify well-supported models of PML nuclear body function based on strict criteria.
Main Methods:
- Literature review of PML protein and PML nuclear body research.
- Analysis of studies investigating PML's role in cellular regulation.
- Application of strict criteria to evaluate proposed models of PML function.
Main Results:
- PML protein acts as a negative growth regulator, inducing G1 cell cycle arrest, senescence, and apoptosis.
- The structural integrity of PML nuclear bodies is essential for normal cellular functions.
- Numerous potential PML partner proteins suggest diverse regulatory roles.
Conclusions:
- PML nuclear bodies are critical for normal cellular functions, with their disruption linked to APL.
- Further research is needed to define a discrete biochemical and molecular model for PML function.
- This review aims to consolidate understanding by focusing on well-supported functional models of PML bodies.