c-myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3.
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.
Sutherland
Kate D
KD
VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Vaillant
François
F
Alexander
Warren S
WS
Wintermantel
Tim M
TM
Forrest
Natasha C
NC
Holroyd
Sheridan L
SL
McManus
Edward J
EJ
Schutz
Gunther
G
Watson
Christine J
CJ
Chodosh
Lewis A
LA
Lindeman
Geoffrey J
GJ
Visvader
Jane E
JE
D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting; D019426:Integrases / Q000378:metabolism; D007774:Lactation / Q000502:physiology; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000502:physiology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases; D020782:Matrix Metalloproteinases