Article

c-myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3.

VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
The EMBO Journal (impact factor: 9.2). 01/2007; 25(24):5805-15. DOI:10.1038/sj.emboj.7601455 pp.5805-15
Source: PubMed

ABSTRACT Suppressor of cytokine signalling (SOCS) proteins are critical attenuators of cytokine-mediated signalling in diverse tissues. To determine the importance of Socs3 in mammary development, we generated mice in which Socs3 was deleted in mammary epithelial cells. No overt phenotype was evident during pregnancy and lactation, indicating that Socs3 is not a key physiological regulator of prolactin signalling. However, Socs3-deficient mammary glands exhibited a profound increase in epithelial apoptosis and tissue remodelling, resulting in precocious involution. This phenotype was accompanied by augmented Stat3 activation and a marked increase in the level of c-myc. Moreover, induction of c-myc before weaning using an inducible transgenic model recapitulated the Socs3 phenotype, and elevated expression of likely c-myc target genes, E2F-1, Bax and p53, was observed. Our data establish Socs3 as a critical attenuator of pro-apoptotic pathways that act in the developing mammary gland and provide evidence that c-myc regulates apoptosis during involution.

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  • Article: SOCS3 is essential in the regulation of fetal liver erythropoiesis.
    J C Marine, C McKay, D Wang, D J Topham, E Parganas, H Nakajima, H Pendeville, H Yasukawa, A Sasaki, A Yoshimura, J N Ihle
    [show abstract] [hide abstract]
    ABSTRACT: SOCS3 (CIS3/JAB2) is an SH2-containing protein that binds to the activation loop of Janus kinases, inhibiting kinase activity, and thereby suppressing cytokine signaling. During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is Epo independent. Transgene-mediated expression blocks fetal erythropoiesis, resulting in embryonic lethality. SOCS3 deletion results in an embryonic lethality at 12-16 days associated with marked erythrocytosis. Moreover, the in vitro proliferative capacity of progenitors is greatly increased. SOCS3-deficient fetal liver stem cells can reconstitute hematopoiesis in lethally irradiated adults, indicating that its absence does not disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages in JAK3-deficient mice also occurs normally. The results demonstrate that SOCS3 is critical in negatively regulating fetal liver hematopoiesis.
    Cell 10/1999; 98(5):617-27. · 32.40 Impact Factor
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Keywords

augmented Stat3 activation
 
c-myc
 
c-myc regulates apoptosis
 
critical attenuator
 
cytokine signalling
 
cytokine-mediated signalling
 
developing mammary gland
 
diverse tissues
 
inducible transgenic model recapitulated
 
key physiological regulator
 
lactation
 
likely c-myc target genes
 
mammary development
 
mammary epithelial cells
 
overt phenotype
 
precocious involution
 
pro-apoptotic pathways
 
Socs3 phenotype
 
tissue remodelling
 
weaning