The Inhibitor of DNA binding (ID) proteins belong to the class V HLH family of transcription factors. Four ID proteins (ID 1-4) are known in humans.Unlike the basic HLH (bHLH) transcription factors, ID proteins lack the basic DNA binding region. They can heterodimerize with class I bHLH transcription factors to form inactive complexes. They thus act as dominant negative inhibitors of the class I bHLH transcription factors. They are also capable of regulating the activity of class II HLH transcription factors (1). Since, class I and II HLH proteins regulate the expression of cell type-specific genes and differentiated phenotype, ID proteins are thought to regulate the cross-talk between the pathways involved in cell growth and differentiation (2).

Aberrant expression of ID proteins are found in many primary tumors and are found to regulate many steps in cancer progression including Neo-angiogenesis, invasion and migration, proliferation and growth, cell-cell interaction and differentiation (3). These include head and neck squamous cell carcinoma (4), esophageal squamous cell carcinoma (5), melanoma (6), hepatocellular carcinonoma (7), pancreatic cancer (8), Ovarian cancer (9), cervical cancer (10), breast cancer (11,12,13,14) and prostate cancer (15, 16).

Among the transcription factors that ID proteins associate with are the Ets family members (ELKs) (17) and paired box family (PAXs)(18). They can also bind to the retiboblastoma and retinoblastoma-like proteins (RBLs), which are thought to be tumor suppressors (19). IDs can also be phosphorylated by CDK2 (20,21).

References

1. Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H.The protein Id: a negative regulator of helix-loop-helix DNA binding proteins.Cell.1,49-59

2. Forrest S, McNamara C.Id family of transcription factors and vascular lesion formation.Arterioscler Thromb Vasc Biol. 11,2014-20.

3. Fong S, Debs RJ, Desprez PY.Id genes and proteins as promising targets in cancer therapy.Trends Mol Med. 8,387-92.

4. Langlands K, Down GA, Kealey T.Id proteins are dynamically expressed in normal epidermis and dysregulated in squamous cell carcinoma.Cancer Res. 21,5929-33.

5. Hu YC, Lam KY, Law S, Wong J, Srivastava G.Identification of differentially expressed genes in esophageal squamous cell carcinoma (ESCC) by cDNA expression array: overexpression of Fra-1, Neogenin, Id-1, and CDC25B genes in ESCC.Clin Cancer Res. 8,2213-21.

6. Polsky D, Young AZ, Busam KJ, Alani RM.The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas.Cancer Res. 16,6008-11.

7. Lee TK, Man K, Ling MT, Wang XH, Wong YC, Lo CM, Poon RT, Ng IO, Fan ST.Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway.Carcinogenesis.11,1729-36.

8. Maruyama H, Kleeff J, Wildi S, Friess H, Büchler MW, Israel MA, Korc M.Id-1 and Id-2 are overexpressed in pancreatic cancer and in dysplastic lesions in chronic pancreatitis.Am J Pathol. 3,815-22.

9. Schindl M, Schoppmann SF, Ströbel T, Heinzl H, Leisser C, Horvat R, Birner P.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. 2,779-85.

10. Schindl M, Oberhuber G, Obermair A, Schoppmann SF, Karner B, Birner P.Overexpression of Id-1 protein is a marker for unfavorable prognosis in early-stage cervical cancer.Cancer Res. 15,5703-6.

11. Lin CQ, Singh J, Murata K, Itahana Y, Parrinello S, Liang SH, Gillett CE, Campisi J, Desprez PY.A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells. Cancer Res. 2000 Mar 1;60(5):1332-40.

12. Schoppmann SF, Schindl M, Bayer G, Aumayr K, Dienes J, Horvat R, Rudas M, Gnant M, Jakesz R, Birner P.Overexpression of Id-1 is associated with poor clinical outcome in node negative breast cancer.Int J Cancer. 6,677-82.

13. Itahana Y, Singh J, Sumida T, Coppe JP, Parrinello S, Bennington JL, Desprez PY.Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells.Cancer Res. 21,7098-105.

14. de Candia P, Solit DB, Giri D, Brogi E, Siegel PM, Olshen AB, Muller WJ, Rosen N, Benezra R.Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors.Proc Natl Acad Sci U S A.21,12337-42.

15. de Candia P, Solit DB, Giri D, Brogi E, Siegel PM, Olshen AB, Muller WJ, Rosen N, Benezra R.Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors.Proc Natl Acad Sci U S A. 21,12337-42.

16. Ouyang XS, Wang X, Lee DT, Tsao SW, Wong YC.Over expression of ID-1 in prostate cancer. J Urol. 6,2598-602.

17. Coppe JP, Itahana Y, Moore DH, Bennington JL, Desprez PY.Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression.Clin Cancer Res. 6,2044-51.

18. Yates PR, Atherton GT, Deed RW, Norton JD, Sharrocks AD.Id helix-loop-helix proteins inhibit nucleoprotein complex formation by the TCF ETS-domain transcription factors.EMBO J. 4,968-76.

19. Roberts EC, Deed RW, Inoue T, Norton JD, Sharrocks AD.Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding.Mol Cell Biol.2,524-33.

20. Lasorella A, Noseda M, Beyna M, Yokota Y, Iavarone A.Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins.Nature. 6804,592-8.

21. Hara E, Hall M, Peters G.Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors.EMBO J. 2,332-42.