The myoglobin of rodents:Lagostomus maximus (viscacha) andSpalax ehrenbergi (mole rat)

Gurnett, Anne; O’Connell, James P.; Harris, David; Lehmann, H.; Joysey, K. A.; Nevo, Eviatar

doi:10.1007/bf01025063

Cited by 32 publications

(16 citation statements)

References 15 publications

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“…This ratio may even be higher in the mole rat neck muscle used for underground digging, as suggested by the 11-fold enhanced Mb mRNA level. The amino acid replacements observed in mole rat Hb and Mb sequences do not seem to be prime mediators of hypoxia adaptation (38,43). The same is probably true for Ngb and Cygb, which display high sequence conservation in the mole rat.…”

Section: Increased Globin Levels In Spalax Indicate a Function In Hypmentioning

confidence: 63%

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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.

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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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Section: Increased Globin Levels In Spalax Indicate a Function In Hypmentioning

confidence: 63%

“…Spalax cDNAs for Ngb, Cygb, and Mb were isolated by RT-PCR from total RNA of brain, liver, and muscle tissues, respectively. PCR primers (SI Materials and Methods) were derived from published globin sequence alignments and the Spalax Mb protein sequence (38). RT-PCR and 5′/3′ RACE products were cloned and sequenced (Starseq).…”

Section: Methodsmentioning

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.

Self Cite

122

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“…These include: genes for the respiratory proteins hemoglobin, myoglobin, neuroglobin and cytoglobin (Gerlach et al, 2006;Gurnett et al, 1984;Hankeln et al, 2005;Kleinschmidt et al, 1984;Nevo et al, 1989), erythropoietin, hypoxia inducible factor1-alpha (Shams et al, 2004(Shams et al, , 2005c, Epo receptors (Ravid et al, 2007;Shams et al, 2005b), vascular endothelial growth factor (Avivi et al, 2005) and its receptor Flk1 (Band et al, 2008). The tumor-suppressor gene p53 in Spalax harbors two amino acid substitutions identical to those found in human tumor cells which results in an increased activation of cell cycle arrest/DNA repair elements and reduced activation of apoptotic genes as compared to human wild type p53 (Ashur-Fabian et al, 2004;Avivi et al, 2007;Magnusson et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Living with stress: Regulation of antioxidant defense genes in the subterranean, hypoxia-tolerant mole rat, Spalax

Schülke

Dreidax

Malik

et al. 2012

Gene

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“…Under the same conditions, Rattus dies after 2-4 h. This capacity to withstand hypoxic conditions exceeds that manifested by many high-altitude and diving mammals. Since its origin some 40 million years ago, Spalax has evolved multiple adaptations to underground life that allows it to survive and carry out intense activities in a highly hypoxic environment (8)(9)(10)(11), including different structure and function of vascular endothelial growth factor (VEGF) (10), hemoglobin (12), haptoglobin (13), myoglobin (14), erythropoietin, neuroglobin, and cytoglobin (unpublished data).…”

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confidence: 99%

Evolution of p53 in hypoxia-stressedSpalaxmimics human tumor mutation

Ashur‐Fabian

Avivi

Trakhtenbrot

et al. 2004

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

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108

134

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The tumor suppressor gene p53 controls cellular response to a variety of stress conditions, including DNA damage and hypoxia, leading to growth arrest and͞or apoptosis. Inactivation of p53, found in 40 -50% of human cancers, confers selective advantage under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its entire life cycle underground at decidedly lower oxygen tensions than any other mammal studied. Because a wide range of respiratory adaptations to hypoxic stress evolved in Spalax, we speculated that it might also have developed hypoxia adaptation mechanisms analogous to the genetic͞epige-netic alterations acquired during tumor progression. Comparing Spalax with human and mouse p53 revealed an arginine (R) to lysine (K) substitution in Spalax (Arg-174 in human) in the DNAbinding domain, identical to known tumor associated mutations. Multiple p53 sequence alignments with 41 additional species confirmed that Arg-174 is highly conserved. Reporter assays uncovered that Spalax p53 protein is unable to induce apoptosisregulating target genes, resulting in no expression of apaf1 and partial expression of puma, pten, and noxa. However, cell cycle arrest and p53 stabilization͞homeostasis genes were overactivated by Spalax p53. Lys-174 was found critical for apaf1 expression inactivation. A DNA-free p53 structure model predicts that Arg-174 is important for dimerization, whereas Spalax Lys-174 prevents such interactions. Similar neighboring mutations found in human tumors favor growth arrest rather than apoptosis. We hypothesize that, in an analogy with human tumor progression, Spalax underwent remarkable adaptive p53 evolution during 40 million years of underground hypoxic life.

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The myoglobin of rodents:Lagostomus maximus (viscacha) andSpalax ehrenbergi (mole rat)

Cited by 32 publications

References 15 publications

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

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

Living with stress: Regulation of antioxidant defense genes in the subterranean, hypoxia-tolerant mole rat, Spalax

Evolution of p53 in hypoxia-stressedSpalaxmimics human tumor mutation

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