p73 Alternative Splicing: Exploring a Biological Role for the C-Terminal Isoforms

• Published in: Journal of molecular biology 2018-06, Vol.430 (13), p.1829-1838
• Main Authors: Vikhreva, Polina, Melino, Gerry, Amelio, Ivano
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Cell Death; Cell Differentiation; Cell Proliferation; Humans; neurodevelopment; p53 family; p73; Protein Domains; splicing isoforms; transcription; Tumor Protein p73 - chemistry; Tumor Protein p73 - genetics; Tumor Protein p73 - metabolism
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2018.04.034

p73 (encoded by TP73 gene) is a p53 related protein that functions as a transcriptional factor. Similarly to p53, following DNA damage, p73 is stabilized and activated and controls expression of target genes that are involved in the regulation of cycle arrest and apoptosis. However, great complexity to the function of this gene is given by the wide range of its non-tumor-related roles, which include neurological development, ciliogenesis and fertility. From the structural point of view, p73 displays an intricate range of regulations because it can be expressed both as an N-terminally deleted dominant-negative isoforms and as multiple alternatively spliced C-terminal isoforms, which can include or not a sterile alpha motif domain. More is known about the functions of the N-terminal isoforms of p73 (TAp73 and ΔNp73) and their opposing pro- and anti-apoptotic roles, whereas the functional differences of the distinct C-terminal splice forms of p73 are very far away from been defined. Here we summarize the current available literature regarding p73 C-terminal isoforms and the contribution of the sterile alpha motif domain to p73 function, trying to provide an unified view in this complex and sometime controversial field. Current data indicate that the full-length, TAp73α, is the major, if not the exclusive, isoform detected in physiological systems, indicating that detailed spatio-temporal expression analysis and functional studies are highly demanded to support a physiological role for the p73 alternative splicing. With this article, we also aim to emphasize the need to further investigation on the topic, refocusing the attention on what we believe are the most relevant unanswered questions. [Display omitted] •p73 is a p53 family member involved in tumor suppression and development.•Alternative splicing and dual promoter usage generate a wide range of p73 isoforms.•Alternative splicing at the C-terminal region of p73 generates at least seven different splice forms.•The current data indicate that the full-length p73 isoform, p73α, is the major expressed form and is required for p73 function.