The ID proteins: Master regulators of cancer stem cells and tumour aggressiveness

Nature Reviews Cancer

Volumn 14, Issue 2, 2014, Pages 77-91

  Lasorella, Anna ^a   Benezra, Robert ^b   Iavarone, Antonio ^a  

^a NewYork Presbyterian Hospital   (United States)

^b MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALS; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; INHIBITOR OF DIFFERENTIATION PROTEINS; NEOPLASMS; NEOPLASTIC STEM CELLS;

EID: 84894527757     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3638     Document Type: Review

References (234)

1. von Hansemann, D. P. On the asymmetrical cell division in epithelial cancers and its biological significance. Virchows Arch. 119, 299-326 (1890).
2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
3. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).
4. Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527-530 (2012).
5. Hu, J. et al. Neutralization of terminal differentiation in gliomagenesis. Proc. Natl Acad. Sci. USA 110, 14520-14527 (2013).
6. Schonberg, D. L., Venere, M. & Rich, J. N. Changing the fate of cancer, one splice at a time. Proc. Natl Acad. Sci. USA 110, 14510-14511 (2013).
7. Barker, N., Bartfeld, S. & Clevers, H. Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell 7, 656-670 (2010).
8. Chambers, I. & Tomlinson, S. R. The transcriptional foundation of pluripotency. Development 136, 2311-2322 (2009).
9. Holmberg, J. & Perlmann, T. Maintaining differentiated cellular identity. Nature Rev. Genet. 13, 429-439 (2012).
10. Kim, J. et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313-324 (2010).
11. Suva, M. L., Riggi, N. & Bernstein, B. E. Epigenetic reprogramming in cancer. Science 339, 1567-1570 (2013).
12. Benezra, R., Davis, R. L., Lockshon, D., Turner, D. L. & Weintraub, H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61, 49-59 (1990).
13. Perk, J., Iavarone, A. & Benezra, R. Id family of helix-loop-helix proteins in cancer. Nature Rev. Cancer 5, 603-614 (2005).
14. Ellis, H. M., Spann, D. R. & Posakony, J. W. extramacrochaetae, a negative regulator of sensory organ development in Drosophila, defines a new class of helix-loop-helix proteins. Cell 61, 27-38 (1990).
15. Garrell, J. & Modolell, J. The Drosophila extramacrochaetae locus, an antagonist of proneural genes that, like these genes, encodes a helix-loop-helix protein. Cell 61, 39-48 (1990).
16. Biggs, J., Murphy, E. V. & Israel, M. A. A human Id-like helix-loop-helix protein expressed during early development. Proc. Natl Acad. Sci. USA 89, 1512-1516 (1992).
17. Christy, B. A. et al. An Id-related helix-loop-helix protein encoded by a growth factor-inducible gene. Proc. Natl Acad. Sci. USA 88, 1815-1819 (1991).
18. Riechmann, V., van Cruchten, I. & Sablitzky, F. The expression pattern of Id4, a novel dominant negative helix-loop-helix protein, is distinct from Id1, Id2 and Id3. Nucleic Acids Res. 22, 749-755 (1994).
19. Sun, X. H., Copeland, N. G., Jenkins, N. A. & Baltimore, D. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol. Cell Biol. 11, 5603-5611 (1991).
20. Massari, M. E. & Murre, C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol. Cell Biol. 20, 429-440 (2000).
21. Norton, J. D., Deed, R. W., Craggs, G. & Sablitzky, F. Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell Biol. 8, 58-65 (1998).
22. Quong, M. W., Romanow, W. J. & Murre, C. E protein function in lymphocyte development. Annu. Rev. Immunol. 20, 301-322 (2002).
23. Engel, I. & Murre, C. The function of E? and Id proteins in lymphocyte development. Nature Rev. Immunol. 1, 193-199 (2001).
24. Gonda, H. et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. J. Exp. Med. 198, 1427-1437 (2003).
25. Ohtani, N. et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409, 1067-1070 (2001).
26. Roberts, E. C., Deed, R. W., Inoue, T., Norton, J. D. & Sharrocks, A. D. Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding. Mol. Cell Biol. 21, 524-533 (2001).
27. Yates, P. R., Atherton, G. T., Deed, R. W., Norton, J. D. & Sharrocks, A. D. Id helix-loop-helix proteins inhibit nucleoprotein complex formation by the TCF ETS-domain transcription factors. EMBO J. 18, 968-976 (1999).
28. O'Brien, P., Morin, P. Jr., Ouellette, R. J. & Robichaud, G. A. The Pax-5 gene: a pluripotent regulator of B-cell differentiation and cancer disease. Cancer Res. 71, 7345-7350 (2011).
29. Iavarone, A., Garg, P., Lasorella, A., Hsu, J. & Israel, M. A. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev. 8, 1270-1284 (1994).
30. Iavarone, A. et al. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 432, 1040-1045 (2004).
31. Lasorella, A., Iavarone, A. & Israel, M. A. Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Mol. Cell Biol. 16, 2570-2578 (1996).
32. Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592-598 (2000).
33. Lasorella, A., Rothschild, G., Yokota, Y., Russell, R. G. & Iavarone, A. Id2 mediates tumor initiation, proliferation, and angiogenesis in Rb mutant mice. Mol. Cell Biol. 25, 3563-3574 (2005).
34. Popova, M. K., He, W., Korenjak, M., Dyson, N. J. & Moon, N. S. Rb deficiency during Drosophila eye development deregulates EMC, causing defects in the development of photoreceptors and cone cells. J. Cell Sci. 124, 4203-4212 (2011).
35. Rothschild, G., Zhao, X., Iavarone, A. & Lasorella, A. E proteins and Id2 converge on p57Kip2 to regulate cell cycle in neural cells. Mol. Cell Biol. 26, 4351-4361 (2006).
36. Hirai, S. et al. RP58 controls neuron and astrocyte differentiation by downregulating the expression of Id1-4 genes in the developing cortex. EMBO J. 31, 1190-1202 (2012).
37. Nam, H. S. & Benezra, R. High levels of Id1 expression define B1 type adult neural stem cells. Cell Stem Cell 5, 515-526 (2009).
38. Niola, F. et al. Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nature Cell Biol. 14, 477-487 (2012).
39. Romero-Lanman, E. E., Pavlovic, S., Amlani, B., Chin, Y. & Benezra, R. Id1 maintains embryonic stem cell self-renewal by up-regulation of Nanog and repression of Brachyury expression. Stem Cells Dev. 21, 384-393 (2012).
40. Suh, H. C. et al. Id1 immortalizes hematopoietic progenitors in vitro and promotes a myeloproliferative disease in vivo. Oncogene 27, 5612-5623 (2008).
41. Williams, S. A. et al. USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell 146, 918-930 (2011).
42. Ying, Q. L., Nichols, J., Chambers, I. & Smith, A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115, 281-292 (2003).
43. Love, C. et al. The genetic landscape of mutations in Burkitt lymphoma. Nature Genet. 44, 1321-1325 (2012).
44. Richter, J. et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nature Genet. 44, 1316-1320 (2012).
45. Schmitz, R. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490, 116-120 (2012).
46. Chadwick, N. et al. Identification of novel Notch target genes in T cell leukaemia. Mol. Cancer 8, 35 (2009).
47. Gautschi, O. et al. Regulation of Id1 expression by SRC: implications for targeting of the bone morphogenetic protein pathway in cancer. Cancer Res. 68, 2250-2258 (2008).
48. Jeon, H. M. et al. Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling. Genes Dev. 22, 2028-2033 (2008).
49. Lasorella, A. et al. Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma. Cancer Res. 62, 301-306 (2002).
50. Meier-Stiegen, F. et al. Activated Notch1 target genes during embryonic cell differentiation depend on the cellular context and include lineage determinants and inhibitors. PLoS ONE 5, e11481 (2010).
51. Reynaud-Deonauth, S. et al. Notch signaling is involved in the regulation of Id3 gene transcription during Xenopus embryogenesis. Differentiation 69, 198-208 (2002).
52. Tam, W. F. et al. Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells. Blood 112, 1981-1992 (2008).
53. Birkenkamp, K. U. et al. FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1. J. Biol. Chem. 282, 2211-2220 (2007).
54. Paolella, B. R. et al. p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells. Stem Cells 29, 1090-1101 (2011).
55. Mathas, S. et al. Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma. Proc. Natl Acad. Sci. USA 106, 5831-5836 (2009).
56. Schuller, H. M. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nature Rev. Cancer 9, 195-205 (2009).
57. Improgo, M. R., Tapper, A. R. & Gardner, P. D. Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. Biochem. Pharmacol. 82, 1015-1021 (2011).
58. Pillai, S. et al. ID1 facilitates the growth and metastasis of non-small cell lung cancer in response to nicotinic acetylcholine receptor and epidermal growth factor receptor signaling. Mol. Cell Biol. 31, 3052-3067 (2011).
59. Ponz-Sarvise, M. et al. Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance. Clin. Cancer Res. 17, 4155-4166 (2011).
60. Trevino, J. G. et al. Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma. Neoplasia 14, 1102-1114 (2012).
61. Rothschild, S. I. et al. MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma. Oncogene 31, 4221-4232 (2012).
62. Rothschild, S. I. et al. MicroRNA-381 represses ID1 and is deregulated in lung adenocarcinoma. J. Thorac Oncol. 7, 1069-1077 (2012).
63. Annibali, D. et al. A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and-103, target the differentiation inhibitor ID2. PLoS ONE 7, e40269 (2012).
64. Heyn, H. et al. MicroRNA miR-335 is crucial for the BRCA1 regulatory cascade in breast cancer development. Int. J. Cancer 129, 2797-2806 (2011).
65. Beger, C. et al. Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc. Natl Acad. Sci. USA 98, 130-135 (2001).
66. Welcsh, P. L. et al. BRCA1 transcriptionally regulates genes involved in breast tumorigenesis. Proc. Natl Acad. Sci. USA 99, 7560-7565 (2002).
67. de Candia, P., Benera, R. & Solit, D. B. A role for Id proteins in mammary gland physiology and tumorigenesis. Adv. Cancer Res. 92, 81-94 (2004).
68. Roldan, G., Delgado, L. & Muse, I. M. Tumoral expression of BRCA1, estrogen receptor a and ID4 protein in patients with sporadic breast cancer. Cancer Biol. Ther. 5, 505-510 (2006).
69. Wen, Y. H. et al. Id4 protein is highly expressed in triple-negative breast carcinomas: possible implications for BRCA1 downregulation. Breast Cancer Res. Treat. 135, 93-102 (2012).
70. Park, S. J., Kim, R. J. & Nam, J. S. Inhibitor of DNAbinding 4 contributes to the maintenance and expansion of cancer stem cells in 4T1 mouse mammary cancer cell line. Lab. Anim. Res. 27, 333-338 (2011).
71. Ren, Y. et al. Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4. Sci. Transl Med. 4,147ra112 (2012).
72. Campo, E. et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 117, 5019-5032 (2011).
73. Bain, G. et al. E2A deficiency leads to abnormalities in aß T-cell development and to rapid development of T-cell lymphomas. Mol. Cell Biol. 17, 4782-4791 (1997).
74. Engel, I. & Murre, C. Disruption of pre-TCR expression accelerates lymphomagenesis in E2A-deficient mice. Proc. Natl Acad. Sci. USA 99, 11322-11327 (2002).
75. Engel, I. & Murre, C. E2A proteins enforce a proliferation checkpoint in developing thymocytes. EMBO J. 23, 202-211 (2004).
76. Herblot, S., Aplan, P. D. & Hoang, T. Gradient of E2A activity in B-cell development. Mol. Cell Biol. 22, 886-900 (2002).
77. Li, J. et al. Mutation of inhibitory helix-loop-helix protein Id3 causes.d T-cell lymphoma in mice. Blood 116, 5615-5621 (2010).
78. Ciarrocchi, A. et al. Id1 restrains p21 expression to control endothelial progenitor cell formation. PLoS ONE 2, e1338 (2007).
79. Funato, N., Ohtani, K., Ohyama, K., Kuroda, T. & Nakamura, M. Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors. Mol. Cell Biol. 21, 7416-7428 (2001).
80. Hertel, C. B., Zhou, X. G., Hamilton-Dutoit, S. J. & Junker, S. Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma. Oncogene 21, 4908-4920 (2002).
81. Liu, Y., Encinas, M., Comella, J. X., Aldea, M. & Gallego, C. Basic helix-loop-helix proteins bind to TrkB and p21(Cip1) promoters linking differentiation and cell cycle arrest in neuroblastoma cells. Mol. Cell Biol. 24, 2662-2672 (2004).
82. Niola, F. et al. Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis. J. Clin. Invest. 123, 405-417 (2013).
83. O'Brien, C. A. et al. ID1 and ID3 regulate the selfrenewal capacity of human colon cancer-initiating cells through p21. Cancer Cell 21, 777-792 (2012).
84. Pagliuca, A., Gallo, P., De Luca, P. & Lania, L. Class A helix-loop-helix proteins are positive regulators of several cyclin-dependent kinase inhibitors' promoter activity and negatively affect cell growth. Cancer Res. 60, 1376-1382 (2000).
85. Chen, S. S. et al. Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL. Blood 117, 862-871 (2011).
86. Yu, L. et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nature Genet. 37, 265-274 (2005).
87. Bounpheng, M. A., Dimas, J. J., Dodds, S. G. & Christy, B. A. Degradation of Id proteins by the ubiquitin-proteasome pathway. FASEB J. 13, 2257-2264 (1999).
88. Trausch-Azar, J. S., Lingbeck, J., Ciechanover, A. & Schwartz, A. L. Ubiquitin-Proteasome-mediated degradation of Id1 is modulated by MyoD. J. Biol. Chem. 279, 32614-32619 (2004).
89. Nakayama, K. I. & Nakayama, K. Ubiquitin ligases: cell-cycle control and cancer. Nature Rev. Cancer 6, 369-381 (2006).
90. Amerik, A. Y. & Hochstrasser, M. Mechanism and function of deubiquitinating enzymes. Biochim. Biophys. Acta 1695, 189-207 (2004).
91. Lasorella, A. et al. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442, 471-474 (2006).
92. Manchado, E., Eguren, M. & Malumbres, M. The anaphase-promoting complex/cyclosome (APC/C): cellcycle-dependent and-independent functions. Biochem. Soc. Trans. 38, 65-71 (2010).
93. Deed, R. W., Hara, E., Atherton, G. T., Peters, G. & Norton, J. D. Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation. Mol. Cell Biol. 17, 6815-6821 (1997).
94. Kong, Y., Cui, H. & Zhang, H. Smurf2-mediated ubiquitination and degradation of Id1 regulates p16 expression during senescence. Aging Cell 10, 1038-1046 (2011).
95. Blank, M. et al. A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20. Nature Med. 18, 227-234 (2012).
96. Wasch, R., Robbins, J. A. & Cross, F. R. The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression. Oncogene 29, 1-10 (2010).
97. Wang, Q. et al. Alterations of anaphase-promoting complex genes in human colon cancer cells. Oncogene 22, 1486-1490 (2003).
98. Hua, H. et al. BMP4 regulates pancreatic progenitor cell expansion through Id2. J. Biol. Chem. 281, 13574-13580 (2006).
99. James, D. et al. Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFß inhibition is Id1 dependent. Nature Biotech. 28, 161-166 (2010).
100. Jankovic, V. et al. Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells. Proc. Natl Acad. Sci. USA 104, 1260-1265 (2007).
101. Perry, S. S. et al. Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance. Blood 110, 2351-2360 (2007).
102. Rawlins, E. L., Clark, C. P., Xue, Y. & Hogan, B. L. The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136, 3741-3745 (2009).
103. Suh, H. C. et al. Cell-nonautonomous function of Id1 in the hematopoietic progenitor cell niche. Blood 114, 1186-1195 (2009).
104. Lyden, D. et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401, 670-677 (1999).
105. Anido, J. et al. TGF-ß receptor inhibitors target the CD44high/Id1high glioma-initiating cell population in human glioblastoma. Cancer Cell 18, 655-668 (2010).
106. Jeon, H. M. et al. ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2. Cancer Res. 71, 3410-3421 (2011).
107. Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69-82 (2007).
108. Chen, S., Lewallen, M. & Xie, T. Adhesion in the stem cell niche: biological roles and regulation. Development 140, 255-265 (2013).
109. Fietz, S. A. & Huttner, W. B. Cortical progenitor expansion, self-renewal and neurogenesis-a polarized perspective. Curr. Opin. Neurobiol. 21, 23-35 (2011).
110. Lathia, J. D. et al. Integrin a 6 regulates glioblastoma stem cells. Cell Stem Cell 6, 421-432 (2010).
111. Park, D. M. & Rich, J. N. Biology of glioma cancer stem cells. Mol. Cells 28, 7-12 (2009).
112. Boettner, B. & Van Aelst, L. Control of cell adhesion dynamics by Rap1 signaling. Curr. Opin. Cell Biol. 21, 684-693 (2009).
113. Barrett, L. E. et al. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell 21, 11-24 (2012).
114. Diaz-Flores, L. Jr. et al. Adult stem and transitamplifying cell location. Histol. Histopathol. 21, 995-1027 (2006).
115. Liu, C. et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146, 209-221 (2011).
116. Benezra, R., Rafii, S. & Lyden, D. The Id proteins and angiogenesis. Oncogene 20, 8334-8341 (2001).
117. Benezra, R. Role of Id proteins in embryonic and tumor angiogenesis. Trends Cardiovasc. Med. 11, 237-241 (2001).
118. Lyden, D. et al. Impaired recruitment of bone-marrowderived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194-1201 (2001).
119. Ruzinova, M. B. et al. Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrowderived endothelial cells in spontaneous murine tumors. Cancer Cell 4, 277-289 (2003).
120. Fontemaggi, G. et al. The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis. Nature Struct. Mol. Biol. 16, 1086-1093 (2009).
121. Jin, X. et al. EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res. 71, 7125-7134 (2011).
122. Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518-524 (2005).
123. Gupta, G. P. et al. ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc. Natl Acad. Sci. USA 104, 19506-19511 (2007).
124. Fong, S. et al. Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. Proc. Natl Acad. Sci. USA 100, 13543-13548 (2003).
125. Gumireddy, K. et al. KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Nature Cell Biol. 11, 1297-1304 (2009).
126. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells-an integrated concept of malignant tumour progression. Nature Rev. Cancer 5, 744-749 (2005).
127. Scheel, C. & Weinberg, R. A. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin. Cancer Biol. 22, 396-403 (2012).
128. Coma, S. et al. Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer Res. 70, 3823-3832 (2010).
129. Kang, Y., Chen, C. R. & Massague, J. A self-enabling TGFß response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol. Cell 11, 915-926 (2003).
130. Padua, D. et al. TGFß primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66-77 (2008).
131. Chang, C., Yang, X., Pursell, B. & Mercurio, A. M. Id2 complexes with the SNAG domain of Snai1 inhibiting Snai1-mediated repression of integrin ß4. Mol. Cell Biol. 33, 3795-3804 (2013).
132. Gervasi, M. et al. JunB contributes to Id2 repression and the epithelial-mesenchymal transition in response to transforming growth factor-ß. J. Cell Biol. 196, 589-603 (2012).
133. Stankic, M. et al. TGFß-Id1 signaling opposes Twist and promotes breast cancer lung colonization via a mesenchymal-to-epithelial transition. Cell Rep. 5,1228-1242 (2013).
134. Jorda, M. et al. Id-1 is induced in MDCK epithelial cells by activated Erk/MAPK pathway in response to expression of the Snail and E47 transcription factors. Exp. Cell Res. 313, 2389-2403 (2007).
135. Xu, J., Lamouille, S. & Derynck, R. TGF-ß-induced epithelial to mesenchymal transition. Cell Res. 19, 156-172 (2009).
136. Bolos, V. et al. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J. Cell Sci. 116, 499-511 (2003).
137. Peinado, H. et al. Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J. Cell Sci. 117, 2827-2839 (2004).
138. Cheung, P. Y., Yip, Y. L., Tsao, S. W., Ching, Y. P. & Cheung, A. L. Id-1 induces cell invasiveness in immortalized epithelial cells by regulating cadherin switching and Rho GTPases. J. Cell Biochem. 112, 157-168 (2011).
139. Cubillo, E. et al. E47 and Id1 interplay in epithelialmesenchymal transition. PLoS ONE 8, e59948 (2013).
140. Di, K., Wong, Y. C. & Wang, X. Id-1 promotes TGF-ß1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells. Exp. Cell Res. 313, 3983-3999 (2007).
141. Gulhati, P. et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 71, 3246-3256 (2011).
142. Lamouille, S., Connolly, E., Smyth, J. W., Akhurst, R. J. & Derynck, R. TGF-ß-induced activation of mTOR complex 2 drives epithelial- mesenchymal transition and cell invasion. J. Cell Sci. 125, 1259-1273 (2012).
143. Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelialmesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725-736 (2012).
144. Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709-724 (2012).
145. Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195-198 (2008).
146. Rafii, S. & Lyden, D. Cancer. A few to flip the angiogenic switch. Science 319, 163-164 (2008).
147. Ahlqvist, K., Saamarthy, K., Syed Khaja, A. S., Bjartell, A. & Massoumi, R. Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer. Oncogene 32, 1601-1608 (2013).
148. Gray, M. J. et al. Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. Oncogene 27, 7192-7200 (2008).
149. Hui, C. M. et al. Id-1 promotes proliferation of p53-deficient esophageal cancer cells. Int. J. Cancer 119, 508-514 (2006).
150. Kim, H. et al. Id-1 regulates Bcl-2 and Bax expression through p53 and NF-.B in MCF-7 breast cancer cells. Breast Cancer Res. Treat. 112, 287-296 (2008).
151. Li, B. et al. Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/AKT signaling pathway. Int. J. Cancer 125, 2576-2585 (2009).
152. Ling, M. T., Kwok, W. K., Fung, M. K., Xianghong, W. & Wong, Y. C. Proteasome mediated degradation of Id-1 is associated with TNFa-induced apoptosis in prostate cancer cells. Carcinogenesis 27, 205-215 (2006).
153. Mern, D. S., Hasskarl, J. & Burwinkel, B. Inhibition of Id proteins by a peptide aptamer induces cell-cycle arrest and apoptosis in ovarian cancer cells. Br. J. Cancer 103, 1237-1244 (2010).
154. Mern, D. S., Hoppe-Seyler, K., Hoppe-Seyler, F., Hasskarl, J. & Burwinkel, B. Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells. Breast Cancer Res. Treat. 124, 623-633 (2010).
155. Sharma, P., Patel, D. & Chaudhary, J. Id1 and Id3 expression is associated with increasing grade of prostate cancer: Id3 preferentially regulates CDKN1B. Cancer Med. 1, 187-197 (2012).
156. Zhang, X. et al. Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells. J. Biol. Chem. 282, 33284-33294 (2007).
157. Lin, J. et al. Inhibitor of differentiation 1 contributes to head and neck squamous cell carcinoma survival via the NF-.B/survivin and phosphoinositide 3-kinase/Akt signaling pathways. Clin. Cancer Res. 16, 77-87 (2010).
158. Monticelli, L. A. et al. Transcriptional regulator Id2 controls survival of hepatic NKT cells. Proc. Natl Acad. Sci. USA 106, 19461-19466 (2009).
159. Swarbrick, A., Roy, E., Allen, T. & Bishop, J. M. Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. Proc. Natl Acad. Sci. USA 105, 5402-5407 (2008).
160. Nair, R. et al. Redefining the expression and function of the inhibitor of differentiation 1 in mammary gland development. PLoS ONE 5, e11947 (2010).
161. Salomon, R., Young, L., Macleod, D., Yu, X. L. & Dong, Q. Probasin promoter-driven expression of ID1 is not sufficient for carcinogenesis in rodent prostate. J. Histochem. Cytochem. 57, 599-604 (2009).
162. Kim, D., Peng, X. C. & Sun, X. H. Massive apoptosis of thymocytes in T-cell-deficient Id1 transgenic mice. Mol. Cell Biol. 19, 8240-8253 (1999).
163. Morrow, M. A., Mayer, E. W., Perez, C. A., Adlam, M. & Siu, G. Overexpression of the helix-loop-helix protein Id2 blocks T cell development at multiple stages. Mol. Immunol. 36, 491-503 (1999).
164. Henke, E. et al. Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo. Nature Biotechnol. 26, 91-100 (2008).
165. de Candia, P. et al. Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors. Proc. Natl Acad. Sci. USA 100, 12337-12342 (2003).
166. Valkov, E., Sharpe, T., Marsh, M., Greive, S. & Hyvonen, M. Targeting protein-protein interactions and fragment-based drug discovery. Top. Curr. Chem. 317, 145-179 (2012).
167. Azzarito, V., Long, K., Murphy, N. S. & Wilson, A. J. Inhibition of a-helix-mediated protein-protein interactions using designed molecules. Nature Chem. 5, 161-173 (2013).
168. Ciarapica, R., Rosati, J., Cesareni, G. & Nasi, S. Molecular recognition in helix-loop-helix and helixloop-helix-leucine zipper domains. Design of repertoires and selection of high affinity ligands for natural proteins. J. Biol. Chem. 278, 12182-12190 (2003).
169. Ciarapica, R. et al. Targeting Id protein interactions by an engineered HLH domain induces human neuroblastoma cell differentiation. Oncogene 28, 1881-1891 (2009).
170. Soucek, L. et al. Modelling Myc inhibition as a cancer therapy. Nature 455, 679-683 (2008).
171. Chen, C. H., Kuo, S. C., Huang, L. J., Hsu, M. H. & Lung, F. D. Affinity of synthetic peptide fragments of MyoD for Id1 protein and their biological effects in several cancer cells. J. Pept. Sci. 16, 231-241 (2010).
172. Geng, H. et al. ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21. Cancer Res. 70, 3239-3248 (2010).
173. Hernandez-Vargas, H. et al. Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int. J. Cancer 119, 1164-1175 (2006).
174. Soroceanu, L. et al. Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target. Cancer Res. 73, 1559-1569 (2013).
175. Yap, W. N. et al. γ-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br. J. Cancer 99, 1832-1841 (2008).
176. Bedford, L. et al. Id4 is required for the correct timing of neural differentiation. Dev. Biol. 280, 386-395 (2005).
177. Liu, H. et al. p53 regulates neural stem cell proliferation and differentiation via BMP-Smad1 signaling and Id1. Stem Cells Dev. 22, 913-927 (2013).
178. Yun, K., Mantani, A., Garel, S., Rubenstein, J. & Israel, M. A. Id4 regulates neural progenitor proliferation and differentiation in vivo. Development 131, 5441-5448 (2004).
179. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149-161 (2004).
180. Cotsarelis, G., Sun, T. T. & Lavker, R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329-1337 (1990).
181. Lim, D. A. et al. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713-726 (2000).
182. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836-841 (2003).
183. Jones, D. L. & Wagers, A. J. No place like home: anatomy and function of the stem cell niche. Nature Rev. Mol. Cell Biol. 9, 11-21 (2008).
184. Morrison, S. J. & Spradling, A. C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598-611 (2008).
185. O'Brien, L. E. & Bilder, D. Beyond the niche: tissue-level coordination of stem cell dynamics. Annu. Rev. Cell Dev. Biol. 29, 107-136 (2013).
186. Voog, J. & Jones, D. L. Stem cells and the niche: a dynamic duo. Cell Stem Cell 6, 103-115 (2010).
187. Hsu, Y. C., Pasolli, H. A. & Fuchs, E. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell 144, 92-105 (2011).
188. Ihrie, R. A. & Alvarez-Buylla, A. Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. Neuron 70, 674-686 (2011).
189. Joshi, P. A., Di Grappa, M. A. & Khokha, R. Active allies: hormones, stem cells and the niche in adult mammopoiesis. Trends Endocrinol. Metab. 23, 299-309 (2012).
190. Kordes, C. & Haussinger, D. Hepatic stem cell niches. J. Clin. Invest. 123, 1874-1880 (2013).
191. Moore, K. A. & Lemischka, I. R. Stem cells and their niches. Science 311, 1880-1885 (2006).
192. Mounier, R., Chretien, F. & Chazaud, B. Blood vessels and the satellite cell niche. Curr. Top. Dev. Biol. 96, 121-138 (2011).
193. Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673-1677 (2009).
194. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677-689 (2006).
195. Guilak, F. et al. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5, 17-26 (2009).
196. Kshitiz et al. Matrix rigidity controls endothelial differentiation and morphogenesis of cardiac precursors. Sci. Signal. 5, ra41 (2012).
197. Higgins, S. et al. Fibroblast growth factor 2 reactivates G1 checkpoint in SK-N-MC cells via regulation of p21, inhibitor of differentiation genes (Id1-3), and epithelium-mesenchyme transition-like events. Endocrinology 150, 4044-4055 (2009).
198. Tournay, O. & Benezra, R. Transcription of the dominant-negative helix-loop-helix protein Id1 is regulated by a protein complex containing the immediate-early response gene Egr-1. Mol. Cell Biol. 16, 2418-2430 (1996).
199. Nishimori, H. et al. The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors. Oncogene 21, 8302-8309 (2002).
200. Langenfeld, E. M., Kong, Y. & Langenfeld, J. Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5. Oncogene 25, 685-692 (2006).
201. Yan, W. et al. High incidence of T-cell tumors in E2A-null mice and E2A/Id1 double-knockout mice. Mol. Cell Biol. 17, 7317-7327 (1997).
202. Hacker, C. et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nature Immunol. 4, 380-386 (2003).
203. Mori, S., Nishikawa, S. I. & Yokota, Y. Lactation defect in mice lacking the helix-loop-helix inhibitor Id2. EMBO J. 19, 5772-5781 (2000).
204. Russell, R. G., Lasorella, A., Dettin, L. E. & Iavarone, A. Id2 drives differentiation and suppresses tumor formation in the intestinal epithelium. Cancer Res. 64, 7220-7225 (2004).
205. Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702-706 (1999).
206. Pan, L., Sato, S., Frederick, J. P., Sun, X. H. & Zhuang, Y. Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene. Mol. Cell Biol. 19, 5969-5980 (1999).
207. Rivera, R. R., Johns, C. P., Quan, J., Johnson, R. S. & Murre, C. Thymocyte selection is regulated by the helix-loop-helix inhibitor protein, Id3. Immunity 12, 17-26 (2000).
208. Fraidenraich, D. et al. Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science 306, 247-252 (2004).
209. Ding, Y. et al. Significance of Id-1 up-regulation and its association with EGFR in bladder cancer cell invasion. Int. J. Oncol. 28, 847-854 (2006).
210. Stighall, M., Manetopoulos, C., Axelson, H. & Landberg, G. High ID2 protein expression correlates with a favourable prognosis in patients with primary breast cancer and reduces cellular invasiveness of breast cancer cells. Int. J. Cancer 115, 403-411 (2005).
211. Umetani, N. et al. Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer. Oncogene 24, 4721-4727 (2005).
212. Zeng, W., Rushing, E. J., Hartmann, D. P. & Azumi, N. Increased inhibitor of differentiation 4 (id4) expression in glioblastoma: a tissue microarray study. J. Cancer 1, 1-5 (2010).
213. Wilson, J. W. et al. Expression of Id helix-loop-helix proteins in colorectal adenocarcinoma correlates with p53 expression and mitotic index. Cancer Res. 61, 8803-8810 (2001).
214. Umetani, N. et al. Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis. Clin. Cancer Res. 10, 7475-7483 (2004).
215. Luo, K. J. et al. Prognostic relevance of Id-1 expression in patients with resectable esophageal squamous cell carcinoma. Ann. Thorac Surg. 93, 1682-1688 (2012).
216. Yang, H. Y. et al. Expression and prognostic values of Id-1 and Id-3 in gastric adenocarcinoma. J. Surg. Res. 167, 258-266 (2011).
217. Li, X. et al. Prognostic significance of Id-1 and its association with EGFR in renal cell cancer. Histopathology 50, 484-490 (2007).
218. Sun, W. et al. Id-1 and the p65 subunit of NF-κB promote migration of nasopharyngeal carcinoma cells and are correlated with poor prognosis. Carcinogenesis 33, 810-817 (2012).
219. Tobin, N. P., Sims, A. H., Lundgren, K. L., Lehn, S. & Landberg, G. Cyclin D1, Id1 and EMT in breast cancer. BMC Cancer 11, 417 (2011).
220. Wang, H., Wang, X. Q., Xu, X. P. & Lin, G. W. ID4 methylation predicts high risk of leukemic transformation in patients with myelodysplastic syndrome. Leuk. Res. 34, 598-604 (2010).
221. Renne, C. et al. Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin's lymphoma. Am. J. Pathol. 169, 655-664 (2006).
222. Lee, K. T. et al. Overexpression of Id-1 is significantly associated with tumour angiogenesis in human pancreas cancers. Br. J. Cancer 90, 1198-1203 (2004).
223. Maruyama, H. et al. Id-1 and Id-2 are overexpressed in pancreatic cancer and in dysplastic lesions in chronic pancreatitis. Am. J. Pathol. 155, 815-822 (1999).
224. Kleeff, J. et al. The helix-loop-helix protein Id2 is overexpressed in human pancreatic cancer. Cancer Res. 58, 3769-3772 (1998).
225. Lee, S. H. et al. The Id3/E47 axis mediates cell-cycle control in human pancreatic ducts and adenocarcinoma. Mol. Cancer Res. 9, 782-790 (2011).
226. Coppe, J. P., Itahana, Y., Moore, D. H., Bennington, J. L. & Desprez, P. Y. Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression. Clin. Cancer Res. 10, 2044-2051 (2004).
227. Yuen, H. F. et al. Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases. Mod. Pathol. 19, 931-941 (2006).
228. Ciarrocchi, A., Piana, S., Valcavi, R., Gardini, G. & Casali, B. Inhibitor of DNA binding-1 induces mesenchymal features and promotes invasiveness in thyroid tumour cells. Eur. J. Cancer 47, 934-945 (2011).
229. Schindl, M. et al. Level of Id-1 protein expression correlates with poor differentiation, enhanced malignant potential, and more aggressive clinical behavior of epithelial ovarian tumors. Clin. Cancer Res. 9, 779-785 (2003).
230. Ding, R. et al. Overexpressed Id-1 is associated with patient prognosis and HBx expression in hepatitis B virus-related hepatocellular carcinoma. Cancer Biol. Ther. 10, 299-307 (2010).
231. Matsuda, Y. et al. Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16. Cancer 104, 1037-1044 (2005).
232. Lee, J. Y. et al. Id-1 activates Akt-mediated Wnt signaling and p27(Kip1) phosphorylation through PTEN inhibition. Oncogene 28, 824-831 (2009).
233. Nieborowska-Skorska, M. et al. Id1 transcription inhibitor-matrix metalloproteinase 9 axis enhances invasiveness of the breakpoint cluster region/abelson tyrosine kinase-transformed leukemia cells. Cancer Res. 66, 4108-4116 (2006).
234. Bai, G. et al. Id sustains Hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of Hes1. Dev. Cell 13, 283-297 (2007).