Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F.
Id proteins (Id1 to Id4) are helix-loop-helix transcription factors that promote metastasis. It was found that Semaphorin 3F (SEMA3F), a potent inhibitor of metastasis, was repressed by Id2. High metastatic human tumor cell lines had relatively high amounts of Id2 and low SEMA3F levels compared with their low metastatic counterparts. No correlation between metastatic potential and expression of the other Id family members was observed. Furthermore, ectopic expression of Id2 in low metastatic tumor cells downregulated SEMA3F and, as a consequence, enhanced their ability to migrate and invade, two requisite steps of metastasis in vivo. Id2 overexpression was driven by the c-myc oncoprotein. SEMA3F was a direct target gene of the E47/Id2 pathway. Two E-box sites, which bind E protein transcription factors including E47, were identified in the promoter region of the SEMA3F gene. E47 directly activated SEMA3F promoter activity and expression and promoted SEMA3F biological activities, including filamentous actin depolymerization, inactivation of RhoA, and inhibition of cell migration. Silencing of SEMA3F inhibited the E47-induced SEMA3F expression and biological activities, confirming that these E47-induced effects were SEMA3F dependent. E47 did not induce expression of the other members of the SEMA3 family. Id2, a dominant-negative inhibitor of E proteins, abrogated the E47-induced SEMA3F expression and biological activities. Thus, high metastatic tumor cells overexpress c-myc, leading to upregulation of Id2 expression; the aberrantly elevated amount of Id2 represses SEMA3F expression and, as a consequence, enhances the ability of tumor cells to migrate and invade.
Coma
Silvia
S
Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Amin
Dhara N
DN
Shimizu
Akio
A
Lasorella
Anna
A
Iavarone
Antonio
A
Klagsbrun
Michael
M
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein; D014158:Transcription, Genetic; D015854:Up-Regulation
C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; C489427:MYC protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C491230:SEMA3F protein, human; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein
Mol Cell Biol. 2006 Jun;26(11):4351-61
16705184
Nature. 2005 Jul 28;436(7050):518-24
16049480
Nature. 2006 Jul 27;442(7101):471-4
16810178
Biochim Biophys Acta. 2005 Jul 25;1730(1):66-76
16005989
J Clin Invest. 2004 Nov;114(9):1260-71
15520858
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13543-8
14578451
Glia. 2002 Jun;38(4):329-38
12007145
Oncogene. 2001 Dec 20;20(58):8326-33
11840325
Cell. 2006 Nov 17;127(4):679-95
17110329
Cancer. 2008 Feb 1;112(3):552-61
18085637
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19506-11
18048329
Nat Rev Cancer. 2005 Aug;5(8):603-14
16034366
Cancer Res. 2000 Nov 1;60(21):5929-33
11085505
Cancer Res. 2000 Mar 1;60(5):1376-82
10728702
Nat Rev Cancer. 2003 Jun;3(6):453-8
12778135
Nature. 2000 Oct 5;407(6804):592-8
11034201
Neoplasia. 2009 Feb;11(2):157-66
19177200
Mol Cell Biol. 1998 Aug;18(8):4577-88
9671467
Clin Cancer Res. 2004 Mar 15;10(6):2044-51
15041724
Cancer Genet Cytogenet. 2007 Apr 15;174(2):100-10
17452250
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4120-5
8633026
Cancer Res. 2006 Nov 15;66(22):10870-7
17108123
Carcinogenesis. 2005 Oct;26(10):1668-76
15905202
Mol Cell Biol. 1997 Oct;17(10):5888-96
9315646
Cancer Cell. 2003 Jun;3(6):525-30
12842081
J Cell Sci. 2009 Jun 1;122(Pt 11):1723-36
19461072
Cancer Res. 2007 Feb 15;67(4):1451-60
17308083
Oncogene. 1996 Mar 21;12(6):1289-97
8649831
Am J Pathol. 1999 Sep;155(3):815-22
10487839
Cell. 2004 Jan 23;116(2):167-79
14744429
Nat Rev Cancer. 2009 Apr;9(4):274-84
19308067
Circ Res. 2008 Sep 12;103(6):624-34
18669923
Cancer Metastasis Rev. 2007 Dec;26(3-4):421-31
17768598
Mod Pathol. 2006 Jul;19(7):931-41
16575399
Cancer Res. 2002 May 1;62(9):2637-43
11980661
Oncogene. 2008 Dec 4;27(57):7192-200
18806828
Cancer Res. 1998 Sep 1;58(17):3769-72
9731481
Cancer Res. 2001 Dec 15;61(24):8803-10
11751402
Cancer Res. 2004 Feb 1;64(3):1008-15
14871832
Br J Cancer. 2007 Nov 19;97(10):1409-15
18000500
Int J Oncol. 2006 Apr;28(4):847-54
16525633
J Biol Chem. 2008 Oct 3;283(40):27230-8
18660502
Cancer Res. 1997 Feb 1;57(3):524-31
9012485
Neoplasia. 2002 Jan-Feb;4(1):82-7
11922394
Cell Mol Life Sci. 2009 Feb;66(4):649-66
18953684
Oncogene. 2002 Nov 28;21(54):8302-9
12447693
Genes Dev. 1994 Jun 1;8(11):1270-84
7926730