Two new p73 splice variants, gamma and delta, with different transcriptional activity.
Vincenzo De Laurenzi,Antonio Costanzo,Daniela Barcaroli,Alessandro Terrinoni,M Falco,Margherita Annicchiarico-Petruzzelli,Massimo Levrero,Gerry Melino +7 more
TLDR
The results suggest that p73 isoforms may be differentially regulated, with four different isoforms capable of interacting among themselves and with p53 and the relative expression level of each splice variant may modulate p73 transcriptional and growth suppression activities by affecting heterodimer formation.Abstract:
p73 has been recently identified as a new structural and functional homologue of the transcription factor p53. It is expressed in either a full-length form, α, or a shorter β mRNA variant, with exon 13 spliced out. Here we report the identification and functional characterization of two new p73 splicing variants, γ (splicing out exon 11) and δ (splicing out exons 11, 12, and 13). Both γ and δ p73 variants are expressed in human peripheral blood lymphocytes, primary keratinocytes, and different tumor cell lines, including neuroblastoma, glioblastoma, melanoma, hepatoma, and leukemia. The expression pattern of the four p73 splicing variants differs in both primary cells of different lineage and established cell lines even within the same type of tumor. A two-hybrid assay was used to characterize the homodimeric and heterodimeric interactions between the p73 variants, and showed that neither p73γ nor p73δ interact with p53, whereas p73γ showed strong interactions with all p73 isoforms, and p73δ binds efficiently p73α and p73γ but only weakly p73β. At the functional level, p73γ is significantly less efficient in activating transcription of the p21Waf1/Cip1 promoter than p53 or p73β, whereas the effect of p73δ is intermediate and comparable to that of p73α. The ability of the different p73 variants to affect cell growth in p53 null osteosarcoma SAOS-2 cells correlates with their transcriptional activity on the p21Waf1/Cip1 promoter: p73β is the most efficient in inhibiting colony formation, whereas p73γ is almost ineffective. Our results suggest that p73 isoforms may be differentially regulated, with four different isoforms capable of interacting among themselves and with p53. The relative expression level of each splice variant may modulate p73 transcriptional and growth suppression activities by affecting heterodimer formation.read more
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p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours
Annie Yang,Nancy Walker,Roderick T. Bronson,Mourad Kaghad,Mariëtte A. Oosterwegel,Jacques Bonnin,Christine Vagner,Helene Bonnet,Pieter Dikkes,Arlene H. Sharpe,Frank McKeon,Daniel Caput +11 more
TL;DR: It is shown that mice functionally deficient for all p73 isoforms exhibit profound defects, including hippocampal dysgenesis, hydrocephalus, chronic infections and inflammation, as well as abnormalities in pheromone sensory pathways, and there is a marked divergence in the physiological functions of the p53 family members.
Journal ArticleDOI
The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage
JianGen Gong,Antonio Costanzo,Hong-Qiong Yang,Gerry Melino,William G. Kaelin,Massimo Levrero,Jean Y. J. Wang +6 more
TL;DR: The results indicate that c-Abl and p73 are components of a mismatch-repair-dependent apoptosis pathway which contributes to cisplatin-induced cytotoxicity.
Journal ArticleDOI
Role for the p53 homologue p73 in E2F-1-induced apoptosis
Meredith S. Irwin,Maria C. Marin,Andrew C. Phillips,Ratnam S. Seelan,David I. Smith,Wanguo Liu,Elsa R. Flores,Kenneth Y. Tsai,Tyler Jacks,Tyler Jacks,Karen H. Vousden,William G. Kaelin,William G. Kaelin +12 more
TL;DR: It is concluded that activation of p73 provides a means for E2F-1 to induce death in the absence of p53, and the transcription of the p53 homologue p73 is induced.
Journal ArticleDOI
The p53/p63/p73 family of transcription factors: overlapping and distinct functions
TL;DR: The p63 and p73 genes are rarely mutated in human cancer, although p73 loss is observed in neuroblastoma and a subtype of T-cell lymphoma, and this family of transcription factors might regulate a common set of genes in response to different extracellular signals and developmental cues.
Journal ArticleDOI
p73: Friend or foe in tumorigenesis
TL;DR: As p53 and its homologue p73 have significant sequence and functional similarities, p73 might also be expected to act as a tumour suppressor, but p73 is activated after DNA damage in a way that is distinct from that of p53.
References
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TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
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Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
Lawrence A. Donehower,Michele Harvey,Betty L. Slagle,Mark J. McArthur,Charles A. Montgomery,Janet S. Butel,Allan Bradley +6 more
TL;DR: Observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
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A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia
Michael B. Kastan,Qimin Zhan,Wafik S. El-Deiry,Tyler Jacks,William V. Walsh,Beverly Plunkett,Bert Vogelstein,Albert J. Fornace +7 more
TL;DR: Three participants are identified (AT gene(s), p53, and GADD45) in a signal transduction pathway that controls cell cycle arrest following DNA damage; abnormalities in this pathway probably contribute to tumor development.