期刊
CELL DEATH AND DIFFERENTIATION
卷 25, 期 1, 页码 144-153出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2017.178
关键词
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资金
- National Heart Lung Blood Institute [R01 HL129223]
- Medical Research Council, UK
- Associazione Italiana per la Ricerca contro il Cancro [AIRC 2014 IG15653, AIRC 5xmille MCO9979, AIRC 2011 IG11955]
- Fondazione Roma malattie Non transmissibili Cronico-Degenerative (NCD)
- DFG [DO 545/8-1]
- Center for Biomolecular Magnetic Resonance (BMRZ)
- Cluster of Excellence Frankfurt (Macromolecular Complexes)
- MRC [MC_U132670600] Funding Source: UKRI
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL129223] Funding Source: NIH RePORTER
- Medical Research Council [MC_U132670600] Funding Source: researchfish
The p53 family of transcription factors (p53, p63 and p73) covers a wide range of functions critical for development, homeostasis and health of mammals across their lifespan. Beside the well-established tumor suppressor role, recent evidence has highlighted novel non-oncogenic functions exerted by p73. In particular, p73 is required for multiciliated cell (MCC) differentiation; MCCs have critical roles in brain and airways to move fluids across epithelial surfaces and to transport germ cells in the reproductive tract. This novel function of p73 provides a unifying cellular mechanism for the disparate inflammatory and immunological phenotypes of p73-deficient mice. Indeed, mice with Trp73 deficiency suffer from hydrocephalus, sterility and chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance since MCCs are essential for cleaning airways from inhaled pollutants, pathogens and allergens. Cross-species genomic analyses and functional rescue experiments identify TAp73 as the master transcriptional integrator of ciliogenesis, upstream of previously known central nodes. In addition, TAp73 shows a significant ability to regulate cellular metabolism and energy production through direct transcriptional regulation of several metabolic enzymes, such as glutaminase-2 and glucose-6 phosphate dehydrogenase. This recently uncovered role of TAp73 in the regulation of cellular metabolism strongly affects oxidative balance, thus potentially influencing all the biological aspects associated with p73 function, including development, homeostasis and cancer. Although through different mechanisms, p63 isoforms also contribute to regulation of cellular metabolism, thus indicating a common route used by all family members to control cell fate. At the structural level, the complexity of p73's function is further enhanced by its ability to form heterotetramers with some p63 isoforms, thus indicating the existence of an intrafamily crosstalk that determines the global outcome of p53 family function. In this review, we have tried to summarize all the recent evidence that have emerged on the novel non-oncogenic roles of p73, in an attempt to provide a unified view of the complex function of this gene within its family.
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