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

Abstract

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.

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

“…As these isoforms lack either the TAD (ΔNp73 α ) or the SAM (TAp73 β ) (Fig. 1b ) 22 , they aid in defining the p73 domain responsible for binding to MCL1. We observed that both ΔNp73 α and TAp73 β Co-IP with the pulldown of MCL1 protein (Fig.…”

“…Furthermore, both the full length TAp73 and the truncated ΔNp73 isoforms can be alternatively spliced at their C-termini (ΔN/TAp73 α , β , δ , ε , ϕ , γ , η ), generating up to seven C-terminal isoforms per N-terminal variant. There are two additional alternatively spliced N-terminal isoforms, ΔEx2-p73 and ΔEx2/3-p73, generating up to 28 hypothetical p73 variants in total 19 , many of which are currently of unknown significance 22 . All of these p73 isoforms retain their DBD and the TD, suggesting that they all maintain the ability to bind DNA and associate with one another 19 , 22 .…”

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

“…p63 is a member of a multigene family that includes p53 and p73. The p63 and p73 were originally identified based on homology to the major functional domains of p53: transactivation (TA), DNA binding (DBD), and oligomerization; all members of this family can present as multiple protein isoforms . p63 exists as two subclasses, TA and ΔNp63, due to the use of alternate gene promoters .…”

“…The p63 and p73 were originally identified based on homology to the major functional domains of p53: transactivation (TA), DNA binding (DBD), and oligomerization 5,12 ; all members of this family can present as multiple protein isoforms. 5,[12][13][14][15] p63 exists as two subclasses, TA and ΔNp63, due to the use of alternate gene promoters. 5 Additional complexity results from c-terminal alternative splicing of transcripts of both the TA and ΔNp63 subclasses, yielding at least 10 distinct isoforms.…”

Sustained protein synthesis and reduced eEF2K levels in TAp73-\- mice brain: a possible compensatory mechanism

“…TAp73 is the longest isoform encoded by the p73 gene, a member of the p53 family of transcription factors [1][2][3], which plays important roles in tumor suppression [4][5][6][7][8] and cellular homeostasis by promoting the expression of genes to regulate metabolism [9][10][11][12][13][14][15][16][17]. The p53 family also includes p53 and p63 that share with p73 the capability of promoting cell cycle arrest and apoptosis following DNA damage [18][19][20][21][22][23][24].…”