Glucocorticoid receptor-mediated expression of caldesmon regulates cell migration via the reorganization of the actin cytoskeleton.
Glucocorticoids (GCs) play important roles in numerous cellular processes, including growth, development, homeostasis, inhibition of inflammation, and immunosuppression. Here we found that GC-treated human lung carcinoma A549 cells exhibited the enhanced formation of the thick stress fibers and focal adhesions, resulting in suppression of cell migration. In a screen for GC-responsive genes encoding actin-interacting proteins, we identified caldesmon (CaD), which is specifically up-regulated in response to GCs. CaD is a regulatory protein involved in actomyosin-based contraction and the stability of actin filaments. We further demonstrated that the up-regulation of CaD expression was controlled by glucocorticoid receptor (GR). An activated form of GR directly bound to the two glucocorticoid-response element-like sequences in the human CALD1 promoter and transactivated the CALD1 gene, thereby up-regulating the CaD protein. Forced expression of CaD, without GC treatment, also enhanced the formation of thick stress fibers and focal adhesions and suppressed cell migration. Conversely, depletion of CaD abrogated the GC-induced phenotypes. The results of this study suggest that the GR-dependent up-regulation of CaD plays a pivotal role in regulating cell migration via the reorganization of the actin cytoskeleton.
Mayanagi
Taira
T
Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Morita
Tsuyoshi
T
Hayashi
Ken'ichiro
K
Fukumoto
Kentaro
K
Sobue
Kenji
K
D000199:Actins / Q000235:genetics / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000199:Actins; D002148:Calmodulin-Binding Proteins; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid
Nat Rev Mol Cell Biol. 2003 Jun;4(6):446-56
12778124
Biochem Biophys Res Commun. 2000 Dec 20;279(2):307-12
11118283
J Cell Physiol. 2005 Jun;203(3):520-8
15521070
Cell. 2001 Jun 29;105(7):851-62
11439182
Cell. 1995 Apr 7;81(1):53-62
7536630
J Cell Biol. 1985 May;100(5):1656-63
2985624
J Cell Sci. 1993 Feb;104 ( Pt 2):595-606
8505382
J Cell Biol. 2006 May 8;173(3):383-94
16651381
Cell Motil Cytoskeleton. 2004 Jul;58(3):143-59
15146534
Cell Motil Cytoskeleton. 2006 Sep;63(9):543-62
16800003
Genes Dev. 1997 Sep 15;11(18):2295-322
9308960
Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12122-6
1465449
Biochem J. 1988 Apr 1;251(1):121-7
3390149
Mol Cell Biol. 2007 Apr;27(7):2442-51
17261597
Endocr Rev. 1998 Jun;19(3):269-301
9626555
J Cell Biol. 1994 Apr;125(2):359-68
8163552
J Biol Chem. 1984 Nov 25;259(22):13656-9
6150036
Proc Natl Acad Sci U S A. 1973 Mar;70(3):641-5
4197624
Science. 2001 May 25;292(5521):1502-6
11379633
Proc Natl Acad Sci U S A. 1981 Sep;78(9):5652-5
6946503
Urology. 2002 Oct;60(4):553-61
12385906
Endocr Rev. 1984 Winter;5(1):25-44
6368214
Proc Natl Acad Sci U S A. 1987 Dec;84(24):9049-53
3321066
Exp Cell Res. 2007 Oct 1;313(16):3432-45
17714703
Oncogene. 2007 Mar 22;26(13):1885-96
17016446
J Biol Chem. 1987 May 25;262(15):7429-37
3584120
Cancer Res. 1984 Jun;44(6):2302-8
6547074
Cell. 1980 Nov;22(2 Pt 2):555-61
6893813
J Endocrinol. 2003 Sep;178(3):347-55
12967328
J Biol Chem. 2002 Mar 1;277(9):7308-17
11744740
J Immunol. 2002 Jan 1;168(1):400-10
11751986
Physiol Rev. 1999 Jan;79(1):1-71
9922367
Trends Cell Biol. 2005 Mar;15(3):138-45
15752977
Endocr Rev. 1993 Oct;14(5):539-63
8262005
Am J Physiol. 1991 Jan;260(1 Pt 1):C151-8
1846268
J Cell Biol. 1995 Dec;131(5):1223-30
8522585
J Cell Sci. 2007 Oct 15;120(Pt 20):3491-9
17928305
N Engl J Med. 2002 Jan 24;346(4):235-42
11807147
J Cell Biol. 2007 Dec 3;179(5):1027-42
18056415
J Steroid Biochem. 1976 Nov-Dec;7(11-12):1117-22
1025357
FEBS Lett. 2007 Aug 7;581(20):3777-82
17631293
Science. 2003 Dec 5;302(5651):1704-9
14657486
Genes Dev. 1995 Jul 1;9(13):1608-21
7628695
J Biol Chem. 1995 Oct 6;270(40):23661-6
7559534
Biochim Biophys Acta. 2004 Oct 21;1680(2):114-28
15488991
Steroids. 2005 May-Jun;70(5-7):407-17
15862824
Trends Pharmacol Sci. 2001 Jan;22(1):32-9
11165670
Proc Natl Acad Sci U S A. 1992 May 1;89(9):3775-9
1315038
J Biol Chem. 1989 May 5;264(13):7490-7
2540194
J Cell Sci. 2004 Jul 15;117(Pt 16):3593-604
15226374
Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):211-7
12588761
Clin Sci (Lond). 1998 Jun;94(6):557-72
9854452
Genes Dev. 2004 Mar 1;18(5):492-7
15037546
J Cell Biochem. 2007 Dec 1;102(5):1290-9
17497700
Nat Cell Biol. 2007 Oct;9(10):1110-21
17909522
Proc Natl Acad Sci U S A. 1984 May;81(10):3133-7
6328499
Nat Rev Cancer. 2003 Dec;3(12):921-30
14737122
Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E971-9
12376324
Oncogene. 2006 Sep 28;25(44):5942-52
16652149
Endocr Rev. 1996 Jun;17(3):245-61
8771358
J Biol Chem. 2007 Mar 16;282(11):8454-63
17224451
J Biol Chem. 1991 Jul 5;266(19):12115-8
2061300