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Hormonal induction and roles of Disabled-2 in lactation and involution.

Tao W, Moore R, Smith ER, Xu XX - PLoS ONE (2014)

Bottom Line: Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution.However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells.We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center, and Department of Cell Biology, Graduate Program in Molecular Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT
Disabled-2 (Dab2) is a widely expressed endocytic adaptor that was first isolated as a 96 KDa phospho-protein, p96, involved in MAPK signal transduction. Dab2 expression is lost in several cancer types including breast cancer, and Dab2 is thought to have a tumor suppressor function. In mammary epithelia, Dab2 was induced upon pregnancy and further elevated during lactation. We constructed mutant mice with a mosaic Dab2 gene deletion to bypass early embryonic lethality and to investigate the roles of Dab2 in mammary physiology. Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution. In primary cultures of mouse mammary epithelial cells, Dab2 proteins were also induced by estrogen, progesterone, and/or prolactin. Dab2 mammary epithelial cells were refractory to growth suppression induced by TGF-beta. However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells. We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

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Related in: MedlinePlus

Compensatory expression of ARH and Numb in Dab2  mammary epithelial cells.Dab2, ARH, and Numb proteins were analyzed by Western blotting of primary mammary epithelial cells isolated from control (dab2 wildtype and heterozygous (dab2 (+/df)) and conditional knockout (dab2 (f/df); Meox2-Cre) 16.5-day pregnant mice. Based on quantitation using Image J and averaging the outputs, Numb increased 2.1-fold and ARH increased 4.3-fold in Dab2  cells.
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pone-0110737-g009: Compensatory expression of ARH and Numb in Dab2 mammary epithelial cells.Dab2, ARH, and Numb proteins were analyzed by Western blotting of primary mammary epithelial cells isolated from control (dab2 wildtype and heterozygous (dab2 (+/df)) and conditional knockout (dab2 (f/df); Meox2-Cre) 16.5-day pregnant mice. Based on quantitation using Image J and averaging the outputs, Numb increased 2.1-fold and ARH increased 4.3-fold in Dab2 cells.

Mentions: The endocytic function of Dab2 may provide manifold functions in mammary glands during lactation, such as nutrient uptake, milk production and secretion, cell growth, survival, and clearance of dead cells and debris. However, only subtle differences in mammary functions were observed between control and Dab2-deficient mice. The lack of more profound defects in Dab2 knockout mammary glands may due to the compensation by other PTB domain containing endocytic adaptors such as Numb and ARH. Indeed, we have found that Numb and ARH protein levels are increased in Dab2 knockout mammary gland epithelial cells (Figure 9). Previously, we have also observed a compensatory expression of Numb and ARH in Dab2- mouse ES cells and embryos [56].


Hormonal induction and roles of Disabled-2 in lactation and involution.

Tao W, Moore R, Smith ER, Xu XX - PLoS ONE (2014)

Compensatory expression of ARH and Numb in Dab2  mammary epithelial cells.Dab2, ARH, and Numb proteins were analyzed by Western blotting of primary mammary epithelial cells isolated from control (dab2 wildtype and heterozygous (dab2 (+/df)) and conditional knockout (dab2 (f/df); Meox2-Cre) 16.5-day pregnant mice. Based on quantitation using Image J and averaging the outputs, Numb increased 2.1-fold and ARH increased 4.3-fold in Dab2  cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216001&req=5

pone-0110737-g009: Compensatory expression of ARH and Numb in Dab2 mammary epithelial cells.Dab2, ARH, and Numb proteins were analyzed by Western blotting of primary mammary epithelial cells isolated from control (dab2 wildtype and heterozygous (dab2 (+/df)) and conditional knockout (dab2 (f/df); Meox2-Cre) 16.5-day pregnant mice. Based on quantitation using Image J and averaging the outputs, Numb increased 2.1-fold and ARH increased 4.3-fold in Dab2 cells.
Mentions: The endocytic function of Dab2 may provide manifold functions in mammary glands during lactation, such as nutrient uptake, milk production and secretion, cell growth, survival, and clearance of dead cells and debris. However, only subtle differences in mammary functions were observed between control and Dab2-deficient mice. The lack of more profound defects in Dab2 knockout mammary glands may due to the compensation by other PTB domain containing endocytic adaptors such as Numb and ARH. Indeed, we have found that Numb and ARH protein levels are increased in Dab2 knockout mammary gland epithelial cells (Figure 9). Previously, we have also observed a compensatory expression of Numb and ARH in Dab2- mouse ES cells and embryos [56].

Bottom Line: Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution.However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells.We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center, and Department of Cell Biology, Graduate Program in Molecular Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT
Disabled-2 (Dab2) is a widely expressed endocytic adaptor that was first isolated as a 96 KDa phospho-protein, p96, involved in MAPK signal transduction. Dab2 expression is lost in several cancer types including breast cancer, and Dab2 is thought to have a tumor suppressor function. In mammary epithelia, Dab2 was induced upon pregnancy and further elevated during lactation. We constructed mutant mice with a mosaic Dab2 gene deletion to bypass early embryonic lethality and to investigate the roles of Dab2 in mammary physiology. Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution. In primary cultures of mouse mammary epithelial cells, Dab2 proteins were also induced by estrogen, progesterone, and/or prolactin. Dab2 mammary epithelial cells were refractory to growth suppression induced by TGF-beta. However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells. We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

Show MeSH
Related in: MedlinePlus