Antiapoptotic Factor Humanin Is Expressed in Normal and Tumoral Pituitary Cells and Protects Them from TNF-α-Induced Apoptosis

Gottardo, María Florencia; Jaita, Gabriela; Magri, María Laura; Zárate, Sandra; Ayala, Mariela Moreno; Ferraris, Jimena; Eijo, Guadalupe; Pisera, Daniel; Seilicovich, Adriana

doi:10.1371/journal.pone.0111548

Cited by 24 publications

(34 citation statements)

References 49 publications

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“…We speculated that embryonic brain outcomes mirror others' findings in adult brain of mHN upregulation after neurologic injury (Chin et al, 2013;Gottardo et al, 2014;Hashimoto et al, 2001). A limitation of having a restricted sample size for sex-specific determinations exists, yet sex-specific differences emerged.…”

Section: Discussionmentioning

confidence: 89%

Murine maternal dietary restriction affects neural Humanin expression and cellular profile

Baldauf

Sondhi

Shin

et al. 2019

J of Neuroscience Research

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To understand the cellular basis for the neurodevelopmental effects of intrauterine growth restriction (IUGR), we examined the global and regional expression of various cell types within murine (Mus musculus) fetal brain. Our model employed maternal calorie restriction to 50% daily food intake from gestation day 10–19, producing IUGR offspring. Offspring had smaller head sizes with larger head:body ratios indicating a head sparing IUGR effect. IUGR fetuses at embryonic day 19 (E19) had reduced nestin (progenitors), β‐III tubulin (immature neurons), Glial fibrillary acidic protein (astrocytes), and O4 (oligodendrocytes) cell lineages via immunofluorescence quantification and a 30% reduction in cortical thickness. No difference was found in Bcl‐2 or Bax (apoptosis) between controls and IUGR, though qualitatively, immunoreactivity of doublecortin (migration) and Ki67 (proliferation) was decreased. In the interest of examining a potential therapeutic peptide, we next investigated a novel pro‐survival peptide, mouse Humanin (mHN). Ontogeny examination revealed highest mHN expression at E19, diminishing by postnatal day 15 (P15), and nearly absent in adult (3 months). Subanalysis by sex at E19 yielded higher mHN expression among males during fetal life, without significant difference between sexes postnatally. Furthermore, female IUGR mice at E19 had a greater increase in cortical mHN versus the male fetus over their respective controls. We conclude that maternal dietary restriction‐associated IUGR interferes with neural progenitors differentiating into the various cellular components populating the cerebral cortex, and reduces cerebral cortical size. mHN expression is developmental stage and sex specific, with IUGR, particularly in the females, adaptively increasing its expression toward mediating a pro‐survival approach against nutritional adversity.

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Section: Discussionmentioning

confidence: 89%

Murine maternal dietary restriction affects neural Humanin expression and cellular profile

Baldauf

Sondhi

Shin

et al. 2019

J of Neuroscience Research

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“…showing inhibition of TNF-α induced apoptosis by HN in anterior pituitary cells gonadectomized female and male rats. [40]…”

Section: Discussionmentioning

confidence: 99%

Effects of humanin on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid in rats

Gültekin

Emre

Çelik

et al. 2017

Saudi J Gastroenterol

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“…The cytoprotective effects of HN and HNr have been described in different cell types including neurons (Zapala et al 2010;Sponne et al 2004), pancreatic β cells (Hoang et al 2010), testicular germ cells, and Leydig cells (Lue et al 2010). We have previously shown that HN exerts an antiapoptotic effect in anterior pituitary cells from both female and male rats as well as in GH3 cells (Gottardo et al 2014).…”

Section: Introductionmentioning

confidence: 98%

Humanin inhibits apoptosis in pituitary tumor cells through several signaling pathways including NF-κB activation

Gottardo

Ayala

Ferraris

et al. 2017

J. Cell Commun. Signal.

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Humanin (HN) and Rattin (HNr), its homologous in the rat, are peptides with cytoprotective action in several cell types such as neurons, lymphocytes and testicular germ cells. Previously, we have shown that HNr is expressed in pituitary cells and that HN inhibited the apoptotic effect of TNF-α in both normal and tumor pituitary cells. The aim of the present study was to identify signaling pathways that mediate the antiapoptotic effect of HN in anterior pituitary cells from ovariectomized rats and in GH3 cells, a somatolactotrope cell line. We assessed the role of STAT3, JNK, Akt and MAPKs as well as proteins of the Bcl-2 family, previously implicated in the antiapoptotic effect of HN. We also evaluated the participation of NF-κB in the antiapoptotic action of HN. STAT3 inhibition reversed the inhibitory effect of HN on TNF-α-induced apoptosis in normal and pituitary tumor cells, indicating that STAT3 signaling pathway mediates the antiapoptotic effect of HN on pituitary cells. Inhibition of NF-κB pathway did not affect action of HN on normal anterior pituitary cells but blocked the cytoprotective effect of HN on TNF-α-induced apoptosis of GH3 cells, suggesting that the NF-κB pathway is involved in HN action in tumor pituitary cells. HN also induced NF-κB-p65 nuclear translocation in these cells. In pituitary tumor cells, JNK and MEK inhibitors also impaired HN cytoprotective action. In addition, HN increased Bcl-2 expression and decreased Bax mitochondrial translocation. Since HN expression in GH3 cells is higher than in normal pituitary cells, we may suggest that through multiple pathways HN could be involved in pituitary tumorigenesis.

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Antiapoptotic Factor Humanin Is Expressed in Normal and Tumoral Pituitary Cells and Protects Them from TNF-α-Induced Apoptosis

Cited by 24 publications

References 49 publications

Murine maternal dietary restriction affects neural Humanin expression and cellular profile

Murine maternal dietary restriction affects neural Humanin expression and cellular profile

Effects of humanin on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid in rats

Humanin inhibits apoptosis in pituitary tumor cells through several signaling pathways including NF-κB activation

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