P53 in blind subterranean mole rats – loss-of-function versus gain-of-function activities on newly cloned Spalax target genes

Avivi, Aaron; Ashur‐Fabian, Osnat; Joel, A.; Trakhtenbrot, Luba; Adamsky, Konstantin; Goldstein, Ido; Amariglio, Ninette; Rechavi, Gideon; Nevo, Eviatar

doi:10.1038/sj.onc.1210045

Cited by 43 publications

(42 citation statements)

References 33 publications

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“…50,51 In addition, a mouse model 52 in which a p53 R174P mutation was introduced, was defective in apoptosis while inducing cell cycle arrest. The expression changes observed in vivo in a series of Spalax target genes are in accordance with our previous in vitro results, 24,26 and the variations observed by different p53 mutants. 53 Inhibition of apoptosis is one of the key features of cancer and in many cancer types where apaf1 loss is evident.…”

Section: Spalax P53 Is Functionally Biased Against Apaf1 and Towards supporting

confidence: 78%

“…45 We have previously demonstrated, in vitro, that Spalax p53 is functionally biased toward G 1 arrest and against apoptosis. 24,26 In particular, we have shown that apaf1, a critical regulator of apoptosis in response to several cellular stresses, including hypoxia, 46 was completely inactivated by Spalax p53. "Humanization" of Spalax p53 at position 174, Figure 3.…”

Section: Methodsmentioning

confidence: 99%

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The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors

2010

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Section: Spalax P53 Is Functionally Biased Against Apaf1 and Towards supporting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors

2010

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“…The subterranean mole rat (Spalax) thus provides a unique natural model, because it has evolved adaptive strategies to cope with extreme underground conditions of hypoxic stress (20). The high tolerance of Spalax to hypoxia seems related to a wide array of respiratory and cardiovascular adaptations, as reflected in structural and functional properties of several hypoxia-related genes including EPO (21), EPO-R (22), VEGF (23,24), HIF-1 (24,25), and p53 (26,27). The sequence of Spalax EPO-R (sEPO-R) exhibits unique features compared with EPO-R of other mammals (22).…”

Section: Erythropoietic Functions Of Erythropoietin (Epo) Are Mediatementioning

confidence: 99%

An extracellular region of the erythropoietin receptor of the subterranean blind mole rat Spalax enhances receptor maturation

Ravid¹,

Shams²,

Califa³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Erythropoietic functions of erythropoietin (EPO) are mediated by its receptor (EPO-R), which is present on the cell surface of erythroid progenitors and induced by hypoxia. We focused on EPO-R from Spalax galili (sEPO-R), one of the four Israeli species of the subterranean blind mole rat, Spalax ehrenbergi superspecies, as a special natural animal model of high tolerance to hypoxia. Led by the intriguing observation that most of the mouse EPO-R (mEPO-R) is retained in the endoplasmic reticulum (ER), we hypothesized that sEPO-R is expressed at higher levels on the cell surface, thus maximizing the response to elevated EPO, which has been reported in this species. Indeed, we found increased cell-surface levels of sEPO-R as compared with mEPO-R by using flow cytometry analysis of BOSC cells transiently expressing HA-tagged EPO-Rs (full length or truncated). We then postulated that unique extracellular sEPO-R sequence features contribute to its processing and cell-surface expression. To map these domains of the sEPO-R that augment receptor maturation, we generated EPO-R derivatives in which parts of the extracellular region of mEPO-R were replaced with the corresponding fragments of sEPO-R. We found that an extracellular portion of sEPO-R, harboring the N-glycosylation site, conferred enhanced maturation and increased transport to the cell surface of the respective chimeric receptor.Taken together, we demonstrate higher surface expression of sEPO-R, attributed at least in part to increased ER exit, mediated by an extracellular region of this receptor. We speculate that these sEPO-R sequence features play a role in the adaptation of Spalax to extreme hypoxia.signal transduction ͉ intracellular trafficking ͉ hypoxia ͉ glycosylation E rythropoietin (EPO) promotes proliferation and differentiation of erythroid cell precursors via activation of its cellsurface receptor (EPO-R) (1, 2). EPO-R is a member of the cytokine-receptor superfamily, characterized by the presence of four conserved Cys residues and a ''WSXWS'' motif in its extracellular domain. The lack of enzymatic activity in the intracellular domain of these receptors necessitates complex formation of ligand-bound receptors with other signaling partners [i.e., Janus kinases (JAKs)] (3) to initiate signaling cascades. EPO-R is synthesized in the endoplasmic reticulum (ER) as a major 64-kDa form with a single endoglycosidase H (Endo H)-sensitive high-mannose oligosaccharide and as a nonglycosylated 62-kDa form. Forty to 60% of the 64-kDa EPO-R molecules undergo further glycan maturation to generate the 66-kDa Endo H-resistant EPO-R (4).In contrast to other type 1 cytokine receptors (5-7), a most striking property of the EPO-R is its low expression on the cell surface (4, 8-10) despite its high intracellular levels. The majority of newly synthesized EPO-R remains sequestered intracellularly and is rapidly degraded (t 1/2 Ϸ 45 min) (11). These metabolic features are similar in both transfected (4) and fetal liver cells that endogenously express the EPO-R (12), suppor...

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“…Hypoxia tolerance mechanisms identified in Spalax as compared with R. norvegicus include blood properties, anatomical and biochemical changes in respiratory organs (2,4), and differences in the structure and function of a growing list of gene products (7)(8)(9)(10). Transcription patterns of genes related to hypoxic stress differ interspecifically in Spalax (5,11) and between Spalax and rat, involving key players such as erythropoietin (Epo) and its receptors, and hypoxia-inducible factor-1α (Hif-1α) (12,13).…”

mentioning

confidence: 99%

Neuroglobin, cytoglobin, and myoglobin contribute to hypoxia adaptation of the subterranean mole rat Spalax

Avivi

Gerlach²,

Joel³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

122

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The subterranean mole rat Spalax is an excellent model for studying adaptation of a mammal toward chronic environmental hypoxia. Neuroglobin (Ngb) and cytoglobin (Cygb) are O 2 -binding respiratory proteins and thus candidates for being involved in molecular hypoxia adaptations of Spalax. Ngb is expressed primarily in vertebrate nerves, whereas Cygb is found in extracellular matrix-producing cells and in some neurons. The physiological functions of both proteins are not fully understood but discussed with regard to O 2 supply, the detoxification of reactive oxygen or nitrogen species, and apoptosis protection. Spalax Ngb and Cygb coding sequences are strongly conserved. However, mRNA and protein levels of Ngb in Spalax brain are 3-fold higher than in Rattus norvegicus under normoxia. Importantly, Spalax expresses Ngb in neurons and additionally in glia, whereas in hypoxia-sensitive rodents Ngb expression is limited to neurons. Hypoxia causes an approximately 2-fold downregulation of Ngb mRNA in brain of rat and mole rat. A parallel regulatory response was found for myoglobin (Mb) in Spalax and rat muscle, suggesting similar functions of Mb and Ngb. Cygb also revealed an augmented normoxic expression in Spalax vs. rat brain, but not in heart or liver, indicating distinct tissue-specific functions. Hypoxia induced Cygb transcription in heart and liver of both mammals, with the most prominent mRNA up-regulation (12-fold) in Spalax heart. Our data suggest that tissue globins contribute to the remarkable tolerance of Spalax toward environmental hypoxia. This is consistent with the proposed cytoprotective effect of Ngb and Cygb under pathological hypoxic/ischemic conditions in mammals.

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P53 in blind subterranean mole rats – loss-of-function versus gain-of-function activities on newly cloned Spalax target genes

Cited by 43 publications

References 33 publications

The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors

The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors

An extracellular region of the erythropoietin receptor of the subterranean blind mole rat Spalax enhances receptor maturation

Neuroglobin, cytoglobin, and myoglobin contribute to hypoxia adaptation of the subterranean mole rat Spalax

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