scholarly journals ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Stephen R. Hennigar ◽  
Young Ah Seo ◽  
Supriya Sharma ◽  
David I. Soybel ◽  
Shannon L. Kelleher
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Mammary Gland Involution

scholarly journals Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution

2001 ◽  
Vol 152 (4) ◽  
pp. 693-703 ◽  
Author(s):  
Caroline M. Alexander ◽  
Sushma Selvarajan ◽  
John Mudgett ◽  
Zena Werb
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Adipocyte Differentiation ◽  
Late Pregnancy ◽  
Gelatinase A ◽  
Stromal Microenvironment ◽  
Mammary Gland Involution ◽  
Targeted Mutation ◽  
The Matrix ◽  
A Cell

The matrix metalloproteinase MMP-3/stromelysin-1 (Str1) is highly expressed during mammary gland involution induced by weaning. During involution, programmed cell death of the secretory epithelium takes place concomitant with the repopulation of the mammary fat pad with adipocytes. In this study, we have used a genetic approach to determine the role of Str1 during mammary involution. Although Str1 has been shown to induce unscheduled apoptosis when expressed ectopically during late pregnancy (Alexander, C.M., E.W. Howard, M.J. Bissell, and Z. Werb. 1996. J. Cell Biol. 135:1669–1677), we found that during post-lactational involution, mammary glands from transgenic mice that overexpress the tissue inhibitor of metalloproteinases, TIMP-1 (TO), or mice carrying a targeted mutation in Str1 showed accelerated differentiation and hypertrophy of adipocytes, while epithelial apoptosis was unaffected. These data suggest that matrix metalloproteinases (MMPs) do not induce unscheduled epithelial cell death after weaning, but instead alter the stromal microenvironment. We used adipogenic 3T3-L1 cells as a cell culture model to test the function of MMPs during adipocyte differentiation. Fibroblastic 3T3-L1 progenitor cells expressed very low levels of MMPs or TIMPs. The transcription of a number of MMP and TIMP mRNAs [Str1, MT1-MMP, (MMP-14) collagenase-3 (MMP-13), gelatinase A (MMP-2), and TIMP-1, -2 and -3] was induced in committed preadipocytes, but only differentiated adipocytes expressed an activated MMP, gelatinase A. The addition of MMP inhibitors (GM 6001 and TIMP-1) dramatically accelerated the accumulation of lipid during differentiation. We conclude that MMPs, especially Str1, determine the rate of adipocyte differentiation during involutive mammary gland remodeling.

scholarly journals ZnT2 is critical for lysosome acidification and biogenesis during mammary gland involution

2018 ◽  
Vol 315 (2) ◽  
pp. R323-R335 ◽  
Author(s):  
Olivia C. Rivera ◽  
Stephen R. Hennigar ◽  
Shannon L. Kelleher
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Mammary Epithelial Cells ◽  
Tissue Remodeling ◽  
Vacuolar Atpase ◽  
Mammary Epithelial ◽  
Direct Role ◽  
Lysosome Biogenesis ◽  
Mammary Gland Involution ◽  
Lactating Mammary Gland

Mammary gland involution, a tightly regulated process of tissue remodeling by which a lactating mammary gland reverts to the prepregnant state, is characterized by the most profound example of regulated epithelial cell death in normal tissue. Defects in the execution of involution are associated with lactation failure and breast cancer. Initiation of mammary gland involution requires upregulation of lysosome biogenesis and acidification to activate lysosome-mediated cell death; however, specific mediators of this initial phase of involution are not well described. Zinc transporter 2 [ZnT2 ( SLC30A2)] has been implicated in lysosome biogenesis and lysosome-mediated cell death during involution; however, the direct role of ZnT2 in this process has not been elucidated. Here we showed that ZnT2-null mice had impaired alveolar regression and reduced activation of the involution marker phosphorylated Stat3, indicating insufficient initiation of mammary gland remodeling during involution. Moreover, we found that the loss of ZnT2 inhibited assembly of the proton transporter vacuolar ATPase on lysosomes, thereby decreasing lysosome abundance and size. Studies in cultured mammary epithelial cells revealed that while the involution signal TNFα promoted lysosome biogenesis and acidification, attenuation of ZnT2 impaired the lysosome response to this involution signal, which was not a consequence of cytoplasmic Zn accumulation. Our findings establish ZnT2 as a novel regulator of vacuolar ATPase assembly, driving lysosome biogenesis, acidification, and tissue remodeling during the initiation of mammary gland involution.

scholarly journals Impaired cell death and mammary gland involution in the absence of Dock1 and Rac1 signaling

2014 ◽  
Vol 5 (8) ◽  
pp. e1375-e1375 ◽  
Author(s):  
H Bagci ◽  
M Laurin ◽  
J Huber ◽  
W J Muller ◽  
J-F Côté
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Mammary Gland Involution

Differential functions of calpain 1 during epithelial cell death and adipocyte differentiation in mammary gland involution

2014 ◽  
Vol 459 (2) ◽  
pp. 355-368 ◽  
Author(s):  
Teresa Arnandis ◽  
Ivan Ferrer-Vicens ◽  
Luis Torres ◽  
Concha García ◽  
Elena R. Garcia-Trevijano ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Epithelial Cell ◽  
Programmed Cell Death ◽  
Adipocyte Differentiation ◽  
Histone H3 ◽  
Tissue Remodelling ◽  
Mammary Gland Involution ◽  
Epithelial Cell Death

The results of the present study unveil novel and important nuclear functions of calpains in tissue remodelling. Although inducing nuclear permeability during programmed cell death, histone H3 is identified as a new target of calpain-1 upon adipocyte differentiation.

Apoptotic cell death and tissue remodelling during mouse mammary gland involution

Development ◽  
1992 ◽  
Vol 115 (1) ◽  
pp. 49-58 ◽  
Author(s):  
R. Strange ◽  
F. Li ◽  
S. Saurer ◽  
A. Burkhardt ◽  
R.R. Friis
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Mammary Gland ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Apoptotic Cell Death ◽  
Dna Integrity ◽  
Fragmentation Pattern ◽  
Tissue Remodelling ◽  
Mammary Gland Involution

During post-lactational mammary gland involution, the bulk of mammary epithelium dies and is reabsorbed. This massive cell death and tissue restructuring was found to be accompanied by a specific pattern of gene expression. Northern blot analysis showed that weaning resulted in a dramatic drop in ODC, a gene involved in synthesis of a component of milk, and the nearly simultaneous induction of SGP-2, a gene associated with apoptotic cell death. These changes were followed by decreases in expression of milk protein genes to basal levels and expression of genes associated with regulation of cell proliferation and differentiation, p53, c-myc and TGF-beta 1. Subsequently, additional genes implicated in stress response, tissue remodelling, and apoptotic cell death were transiently expressed, expression peaking at about 6 days post-weaning. A non-random degradation of DNA yielding the oligonucleosomal length fragmentation pattern typical of apoptotic cell death (Wyllie, 1980; Wyllie et al., 1980) was detected in association with morphological changes and gene expression. The correlations between: (a) changes in morphology, (b) pattern of gene expression and (c) changes in DNA integrity suggest that complementary programs for cell death and tissue remodelling direct post-lactational mammary gland involution.

scholarly journals Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution

Development ◽  
2011 ◽  
Vol 139 (2) ◽  
pp. 269-275 ◽  
Author(s):  
J. O'Brien ◽  
H. Martinson ◽  
C. Durand-Rougely ◽  
P. Schedin
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Epithelial Cell ◽  
Mammary Gland Involution ◽  
Epithelial Cell Death

Chapter 15 Programmed Cell Death during Mammary Gland Involution

1995 ◽  
pp. 355-368 ◽  
Author(s):  
Robert Strange ◽  
Robert R. Friis ◽  
Lynne T. Bemis ◽  
F. Jon Geske
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Programmed Cell Death ◽  
Mammary Gland Involution

scholarly journals Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution

1997 ◽  
Vol 94 (7) ◽  
pp. 3425-3430 ◽  
Author(s):  
M. Li ◽  
X. Liu ◽  
G. Robinson ◽  
U. Bar-Peled ◽  
K.-U. Wagner ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Programmed Cell Death ◽  
Mammary Gland Involution
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