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IRE1 phosphatase PP2Ce regulates adaptive ER stress response in the postpartum mammary gland.

Ren S, Lu G, Ota A, Zhou ZH, Vondriska TM, Lane TF, Wang Y - PLoS ONE (2014)

Bottom Line: We recently reported that the PPM1l gene encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (named PP2Ce) with highly specific activity towards Inositol-requiring protein-1 (IRE1) and regulates the functional outcome of ER stress.In the present report, we found that the PP2Ce protein is highly expressed in lactating epithelium of the mammary gland.This study provides the first in vivo evidence that PP2Ce is an essential regulator of normal lactation, possibly involving IRE1 signaling and ER stress regulation in mammary epithelium.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America.

ABSTRACT
We recently reported that the PPM1l gene encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (named PP2Ce) with highly specific activity towards Inositol-requiring protein-1 (IRE1) and regulates the functional outcome of ER stress. In the present report, we found that the PP2Ce protein is highly expressed in lactating epithelium of the mammary gland. Loss of PP2Ce in vivo impairs physiological unfolded protein response (UPR) and induces stress kinase activation, resulting in loss of milk production and induction of epithelial apoptosis in the lactating mammary gland. This study provides the first in vivo evidence that PP2Ce is an essential regulator of normal lactation, possibly involving IRE1 signaling and ER stress regulation in mammary epithelium.

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Stress signaling activation in postpartum PP2Ce deficient mammary gland.A. Immunoblot of phospho-JNK, phospho-p38 and Caspase 12 activation (cleaved) levels in PP2Ce +/+ and PP2Ce -/- mammary tissue at day 0 (L0) or day 2 post parturition (L2). B. Quantification of signaling activation from at least 3 samples from each group. #, p<0.05 WT vs. KO.
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pone-0111606-g006: Stress signaling activation in postpartum PP2Ce deficient mammary gland.A. Immunoblot of phospho-JNK, phospho-p38 and Caspase 12 activation (cleaved) levels in PP2Ce +/+ and PP2Ce -/- mammary tissue at day 0 (L0) or day 2 post parturition (L2). B. Quantification of signaling activation from at least 3 samples from each group. #, p<0.05 WT vs. KO.

Mentions: To determine the underlying mechanisms for the defects observed in PP2Ce KO mammary gland, we examined the effect of PP2Ce deficiency on stress signaling. In agreement with our previous in vitro study, where PP2Ce KO MEF cells had elevated stress-kinase signaling upon ER stressor stimulation [25], stress kinases were significantly induced in postpartum PP2Ce KO mammary gland compared to WT controls (Figure 6). Correlated with induced IRE1α expression (Figure 2B), downstream UPR genes including BiP and EDEM are significantly induced in postpartum wildtype mammary gland (Figure 7); induction of these genes, including IRE1α was markedly blunted in the PP2Ce KO mice (Figure 2B and Figure 7). In contrast, there is trend for the induction of pathological ER stress signaling marker CHOP in the mammary gland of postpartum PP2Ce KO mice (Figure 7). All this evidence suggests that PP2Ce is essential for adaptive ER stress response at the onset of lactation and its deficiency can trigger pathological stress signaling in the postpartum mammary gland.


IRE1 phosphatase PP2Ce regulates adaptive ER stress response in the postpartum mammary gland.

Ren S, Lu G, Ota A, Zhou ZH, Vondriska TM, Lane TF, Wang Y - PLoS ONE (2014)

Stress signaling activation in postpartum PP2Ce deficient mammary gland.A. Immunoblot of phospho-JNK, phospho-p38 and Caspase 12 activation (cleaved) levels in PP2Ce +/+ and PP2Ce -/- mammary tissue at day 0 (L0) or day 2 post parturition (L2). B. Quantification of signaling activation from at least 3 samples from each group. #, p<0.05 WT vs. KO.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4219728&req=5

pone-0111606-g006: Stress signaling activation in postpartum PP2Ce deficient mammary gland.A. Immunoblot of phospho-JNK, phospho-p38 and Caspase 12 activation (cleaved) levels in PP2Ce +/+ and PP2Ce -/- mammary tissue at day 0 (L0) or day 2 post parturition (L2). B. Quantification of signaling activation from at least 3 samples from each group. #, p<0.05 WT vs. KO.
Mentions: To determine the underlying mechanisms for the defects observed in PP2Ce KO mammary gland, we examined the effect of PP2Ce deficiency on stress signaling. In agreement with our previous in vitro study, where PP2Ce KO MEF cells had elevated stress-kinase signaling upon ER stressor stimulation [25], stress kinases were significantly induced in postpartum PP2Ce KO mammary gland compared to WT controls (Figure 6). Correlated with induced IRE1α expression (Figure 2B), downstream UPR genes including BiP and EDEM are significantly induced in postpartum wildtype mammary gland (Figure 7); induction of these genes, including IRE1α was markedly blunted in the PP2Ce KO mice (Figure 2B and Figure 7). In contrast, there is trend for the induction of pathological ER stress signaling marker CHOP in the mammary gland of postpartum PP2Ce KO mice (Figure 7). All this evidence suggests that PP2Ce is essential for adaptive ER stress response at the onset of lactation and its deficiency can trigger pathological stress signaling in the postpartum mammary gland.

Bottom Line: We recently reported that the PPM1l gene encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (named PP2Ce) with highly specific activity towards Inositol-requiring protein-1 (IRE1) and regulates the functional outcome of ER stress.In the present report, we found that the PP2Ce protein is highly expressed in lactating epithelium of the mammary gland.This study provides the first in vivo evidence that PP2Ce is an essential regulator of normal lactation, possibly involving IRE1 signaling and ER stress regulation in mammary epithelium.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America.

ABSTRACT
We recently reported that the PPM1l gene encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (named PP2Ce) with highly specific activity towards Inositol-requiring protein-1 (IRE1) and regulates the functional outcome of ER stress. In the present report, we found that the PP2Ce protein is highly expressed in lactating epithelium of the mammary gland. Loss of PP2Ce in vivo impairs physiological unfolded protein response (UPR) and induces stress kinase activation, resulting in loss of milk production and induction of epithelial apoptosis in the lactating mammary gland. This study provides the first in vivo evidence that PP2Ce is an essential regulator of normal lactation, possibly involving IRE1 signaling and ER stress regulation in mammary epithelium.

Show MeSH