p73 cooperates with Ras in the activation of MAP kinase signaling cascade

Fernández-García, Belén; Vaqué, José P.; Herreros-Villanueva, Marta; Marques-Garcia, F; Castrillo, F.; Fernández‐Medarde, Alberto; León, Javier; Marín, María C.

doi:10.1038/sj.cdd.4401945

Cited by 24 publications

(27 citation statements)

References 39 publications

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“…We examined phosphorylated ERK1/2 as a downstream indicator of VEGF signaling 42 and, as published, 43 both p73 isoforms regulated this pathway (Figure 7a). VEGF-A levels were strongly downregulated upon total p73 and DNp73 silencing, (Figures 7a and b), and barely affected after TAp73KD (Figure 7b), pointing to DNp73 as the predominant regulator on HUVEC normoxic cultures.…”

Section: Resultsmentioning

confidence: 99%

“…Western blotting was performed as previously described 43 with the following primary antibodies: rabbit anti-pSmad1/5 (Ser463-/465) 1 : 1000 (Cell Signaling, Danvers, MA, USA), rabbit anti Smad1 1 : 1000 (Cell Signaling), mouse anti-pERK 1 : 1000 (Santa Cruz Biotechnology), rabbit anti-ERK1 : 10 000 (Santa Cruz Biotechnology), rabbit anti-VEGF-A 1 : 1000 (Abcam) mouse anti DNp73 1 : 1000 (Imgenex, San Diego, CO, USA), and rabbit anti Nanog 1 : 1000 (Chemicon, Billerica, TX, USA) followed by the appropriate HRPconjugated secondary antibodies (Pierce, Waltham, MA, USA). The enhanced chemiluminescence was detected with Super Signal West-Pico Chemiluminiscent Substrate (Pierce).…”

Section: Methodsmentioning

confidence: 99%

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p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

et al. 2015

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Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-β and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

et al. 2015

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“…p73 maintains a specific role in cellular differentiation and development (22,80,81). The regulation of cellular differentiation has been described as a mechanism of tumor suppression (82).…”

Section: Discussionmentioning

confidence: 99%

“…Plasmids and Transfection-The cDNAs from human HATAp73␣, TAp73␣292, HA-⌬Np73␣, and pcDNA3-HATAp73⑀ were described previously (22). The reporter plasmid GATA1-Luc (a gift from Dr. T. Nakano, Osaka University) contains a fragment of the GATA1 promoter, including three GATA1-binding sites (23).…”

Section: Mice Husbandry and Dissection Of Hematopoietic Tissue-mentioning

confidence: 99%

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p73 Plays a Role in Erythroid Differentiation through GATA1 Induction

Garcia

Ferrándiz

Fernandez-Alonso

et al. 2009

Journal of Biological Chemistry

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The TP73 gene gives rise to transactivation domain-p73 isoforms (TAp73) as well as ⌬Np73 variants with a truncated N terminus. Although TAp73␣ and -␤ proteins are capable of inducing cell cycle arrest, apoptosis, and differentiation, ⌬Np73 acts in many cell types as a dominant-negative repressor of p53 and TAp73. It has been proposed that p73 is involved in myeloid differentiation, and its altered expression is involved in leukemic degeneration. However, there is little evidence as to which p73 variants (TA or ⌬N) are expressed during differentiation and whether specific p73 isoforms have the capacity to induce, or hinder, this differentiation in leukemia cells. In this study we identify GATA1 as a direct transcriptional target of TAp73␣. Furthermore, TAp73␣ induces GATA1 activity, and it is required for erythroid differentiation. Additionally, we describe a functional cooperation between TAp73 and ⌬Np73 in the context of erythroid differentiation in human myeloid cells, K562 and UT-7. Moreover, the impaired expression of GATA1 and other erythroid genes in the liver of p73KO embryos, together with the moderated anemia observed in p73KO young mice, suggests a physiological role for TP73 in erythropoiesis.

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A novel TAp73‐inhibitory compound counteracts stemness features of glioblastoma stem cells

Villoch‐Fernandez,

Martínez‐García,

Martín‐López

et al. 2024

Molecular Oncology

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Glioblastoma (GB) is the most common and fatal type of primary malignant brain tumor for which effective therapeutics are still lacking. GB stem cells, with tumor‐initiating and self‐renewal capacity, are mostly responsible for GB malignancy, representing a crucial target for therapies. The TP73 gene, which is highly expressed in GB, gives rise to the TAp73 isoform, a pleiotropic protein that regulates neural stem cell biology; however, its role in cancer has been highly controversial. We inactivated TP73 in human GB stem cells and revealed that TAp73 is required for their stemness potential, acting as a regulator of the transcriptional stemness signatures, highlighting TAp73 as a possible therapeutic target. As proof of concept, we identified a novel natural compound with TAp73‐inhibitory capacity, which was highly effective against GB stem cells. The treatment reduced GB stem cell‐invasion capacity and stem features, at least in part by TAp73 repression. Our data are consistent with a novel paradigm in which hijacking of p73‐regulated neurodevelopmental programs, including neural stemness, might sustain tumor progression, pointing out TAp73 as a therapeutic strategy for GB.

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p73 cooperates with Ras in the activation of MAP kinase signaling cascade

Cited by 24 publications

References 39 publications

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

p73 Plays a Role in Erythroid Differentiation through GATA1 Induction

A novel TAp73‐inhibitory compound counteracts stemness features of glioblastoma stem cells

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