Stat5 promotes survival of mammary epithelial cells through transcriptional activation of a distinct promoter in Akt1.
The signal transducer and activator of transcription 5 (Stat5) plays a pivotal role in the proliferation, secretory differentiation, and survival of mammary epithelial cells. However, there is little information about Stat5 target genes that facilitate these biological processes. We provide here experimental evidence that the prolactin-mediated phosphorylation of Stat5 regulates the transcriptional activation of the Akt1 gene. Stat5 binds to consensus sequences within the Akt1 locus in a growth factor-dependent manner to initiate transcription of a unique Akt1 mRNA from a distinct promoter, which is only active in the mammary gland. Elevating the levels of active Akt1 restores the expression of cyclin D1 and proliferation of Jak2-deficient mammary epithelial cells, which provides evidence that Akt1 acts downstream of Jak/Stat signaling. The ligand-inducible expression of Stat5 in transgenic females mediates a sustained upregulation of Akt1 in mammary epithelial cells during the onset of postlactational involution. Stat5-expressing mammary glands exhibit a delay in involution despite induction of proapoptotic signaling events. Collectively, the results of the present study elucidate an underlying mechanism by which active Stat5 mediates evasion from apoptosis and self-sufficiency in growth signals.
Creamer
Bradley A
BA
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198-5950, USA.
Sakamoto
Kazuhito
K
Schmidt
Jeffrey W
JW
Triplett
Aleata A
AA
Moriggl
Richard
R
Wagner
Kay-Uwe
KU
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016384:Consensus Sequence; D019938:Cyclin D1 / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D053614:Janus Kinase 2 / Q000172:deficiency / Q000378:metabolism; D007774:Lactation / Q000187:drug effects / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D008954:Models, Biological; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011981:Receptors, Prolactin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D019938:Cyclin D1; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D004318:Doxycycline
Mol Cell Biol. 2004 Sep;24(18):8037-47
15340066
Oncogene. 2001 Apr 19;20(17):2080-90
11360192
Genesis. 2009 Apr;47(4):234-45
19208431
Mol Cell Biol. 2000 Jan;20(1):389-401
10594041
Oncogene. 2002 Jun 20;21(27):4335-9
12082622
Biochem J. 2000 Jan 1;345 Pt 1:17-24
10600634
Cancer Cell. 2005 Jan;7(1):87-99
15652752
Oncogene. 1993 Mar;8(3):745-54
8437858
Mol Endocrinol. 2001 Jun;15(6):867-81
11376107
Curr Opin Cell Biol. 2001 Apr;13(2):211-7
11248555
Mol Endocrinol. 2002 Apr;16(4):774-84
11923474
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3425-30
9096410
Nat Rev Mol Cell Biol. 2005 Sep;6(9):715-25
16231422
Dev Cell. 2002 Dec;3(6):877-87
12479812
Endocr Rev. 2003 Feb;24(1):1-27
12588805
Cell Cycle. 2005 Jul;4(7):897-900
15970662
Nat Cell Biol. 2005 Apr;7(4):392-8
15793565
Mol Cell Biol. 1995 Apr;15(4):2063-70
7891701
J Cell Biol. 2001 Nov 12;155(4):531-42
11706048
Mol Endocrinol. 2007 Aug;21(8):1877-92
17519353
Cancer Res. 2009 Aug 15;69(16):6642-50
19638583
Semin Cell Dev Biol. 2008 Aug;19(4):401-6
18723104
Nature. 2001 Jun 28;411(6841):1017-21
11429595
Mol Cell Biol. 2001 Mar;21(6):2203-12
11238953
Int J Cancer. 2004 Feb 20;108(5):665-71
14696092
Mol Cell Biol. 2004 Jan;24(1):320-9
14673165
Oncogene. 2002 Jan 10;21(2):198-206
11803463
Oncogene. 2002 Jan 10;21(2):291-8
11803472
J Clin Oncol. 2004 Jun 1;22(11):2053-60
15169792
Mol Cancer Res. 2002 Nov;1(1):32-47
12496367
Cell Growth Differ. 1999 Oct;10(10):685-94
10547072
Cancer Res. 2007 Jan 1;67(1):167-77
17210696
Mol Cell Biol. 2001 Oct;21(20):6859-69
11564870
Mol Endocrinol. 2004 May;18(5):1171-84
14963111
Annu Rev Biochem. 1995;64:621-51
7574495
Genes Dev. 1999 Oct 1;13(19):2604-16
10521404
Cancer Res. 2004 May 1;64(9):3171-8
15126356
J Mammary Gland Biol Neoplasia. 2005 Jan;10(1):25-36
15886884
Biol Reprod. 2004 Mar;70(3):718-28
14613905
Development. 1996 Jan;122(1):181-93
8565829
Genes Dev. 2009 Oct 15;23(20):2382-7
19833766
Mol Cell Biol. 2004 Jun;24(12):5510-20
15169911
Cell. 2000 Jan 7;100(1):57-70
10647931
Endocrinology. 2002 Sep;143(9):3641-50
12193580
Int J Cancer. 2007 Nov 1;121(9):1892-902
17640063
Int J Cancer. 2004 Nov 20;112(4):607-19
15382041
Nature. 1996 Oct 24;383(6602):726-8
8878484
Oncogene. 2008 Feb 21;27(9):1231-42
17724472
Mol Cancer. 2005 Feb 01;4(1):6
15686596
Science. 2002 May 31;296(5573):1653-5
12040185
J Cell Physiol. 2008 Nov;217(2):468-77
18561256
Cell Metab. 2006 Dec;4(6):475-90
17141631
Mol Endocrinol. 2002 Mar;16(3):563-70
11875116
Genes Dev. 1998 Nov 15;12(22):3499-511
9832503