p73 Plays a Role in Erythroid Differentiation through GATA1 Induction

Abstract

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.

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

“…8 The maximal interference using these siRNAs occurs 72 h after transfection, lasting more than 48 h. 8 All angiogenic assays were carried out during this period. It is important to point out that p73KD did not affect HUVEC proliferation kinetics within this time frame (Supplementary figure 3).…”

“…EBs on glass slides (days [8][9][10][11][12] or EBs in collagen gels (days [12][13][14][15][16][17][18][19][20] were fixed with 3.7% PFA and processed for whole-mount immunohistochemical staining as previously described. 59 The samples were analyzed in a LSM 510 META confocal microscope (Carl Zeiss, Jena, Germany).…”

“…14 These mice, which lack all p73 isoforms, exhibit gastrointestinal and cranial hemorrhages, 14 suggestive of vascular fragility. Furthermore, TAp73 directly regulates GATA-1, 8 which is essential for endothelial and hematopoietic differentiation. 15,16 This compounded information led us to hypothesize that p73 could be implicated in the regulation of vasculogenesis/angiogenesis.…”

The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation

“…[28] Interestingly, p73 contributes to myeloid differentiation by modulating p21 CIP1 , and RBM38 may contribute to this process by regulating p73 mRNA stability. [29], [30] Although limited information is available on the role of DND1 in tumors, DND1 mutations have been implicated in germ cell loss and testicular germ cell tumors. [31] This effect has been partially explained by inhibiting miRNA mediated cleavage of mRNAs bound by DND1.…”

Regulatory feedback loop between TP73 and TRIM32

“…The TA proteins are transactivation competent, 3, 4, 5, 6, 7 whereas the DN isoforms can have dominant-negative function towards p53 and TAp73, 8, 9 acting as a major survival factor in postmitotic neurons, 10 or transactivating target genes in a cell context-dependent manner. 7, 11 Thus, the TA/ΔN differential expression is crucial for determining p73 function. This regulation can operate at transcriptional 12 or post-transcriptional levels.…”