Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Retinoblastoma Tumor Suppressor Protein (RB)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101891


Historical Background

Isoforms of the retinoblastoma tumor suppressor protein (RB) have meanwhile been identified in many different species. As far as human RB is concerned, its gene has been found on chromosome 13 in 1983 (Cavenee et al. 1983). Subsequently, the sequences of the human RB gene and its encoded RB protein (encompassing 928 amino acids) have been communicated in 1986 (Friend et al. 1986) and, respectively, 1987 (Lee et al. 1987a). In the following 2 years, two important functional aspects of RB have been unveiled: its cell cycle-dependent phosphorylation (Chen et al. 1989; deCaprio et al. 1989) and its physical interaction with viral oncoproteins such as the E7 protein of the human papillomavirus (HPV) type 16 (Dyson et al. 1989). Within this same period, it was also discovered that the introduction of the intact RB gene into various tumor cells, e.g., human prostate carcinoma cells (Bookstein et al. 1990), suppresses their growth. This insight stimulated further studies along these lines which demonstrated that both the RB protein (Antelman et al. 1995) and RB-derived peptides (Radulescu and Jaques 2000, 2003; Radulescu et al. 2000; Radulescu 2008, 2014; Radulescu and Fahraeus 2010) are able to block cancer cell proliferation, consistent with the physiological arrest in the G1 phase of the cell cycle and the associated restriction point control accomplished by natural (hypo-phosphorylated) RB.

Crucial Functional Aspects of RB

Tumor Suppression

As outlined above, RB is able to suppress the growth of various tumor cells, and, conversely, its functional network (the so-called RB pathway that comprises the cyclin D1, Cdk4, p16, and RB proteins as well as the E2F transcription factor) is found to be inactivated in the majority of most tumors, thus making this molecular disturbance a common denominator of carcinogenesis (Sherr 1996). Some of these neoplasias, e.g., retinoblastomas (Sherr 1996), osteosarcomas (Sherr 1996), pancreatic carcinomas (Sherr 1996, Schutte et al. 1997), and lung cancers (Sherr 1996, Kaye 2002), are paradigmatic in that they display a very high percentage (close to 100%) of RB pathway defects. Hence, the RB pathway epitomizes what has been anticipated in the early 1980s, i.e., many years before its discovery, which is “that all forms of cancer, in whatever organs and of whatever cell types, are a single disease, caused by a single, central controlling mechanism gone wrong” (Thomas 1983). In the same context, it was, moreover, predicted that “this level of deep information will begin to generate pharmacologic ideas aimed at switching the mechanism off, or turning it around, and when this point is reached, we can begin talking about “a” cancer cure” (Thomas 1983), an insight which was later vindicated by the advent of broadly effective RB-based anticancer therapeutics in the 1990s (Antelman et al. 1995; Radulescu and Jaques 2000, 2003; Radulescu et al. 2000; Radulescu 2008, 2014; Radulescu and Fahraeus 2010).

Promotion of Neuronal Survival and Differentiation

In this context, it has been shown that RB is essential both for neuron survival and differentiation (Lee et al. 1994a; Slack et al. 1998). Accordingly, it may represent an important template in future strategies aimed at counteracting pathological forms of neuronal apoptosis such as during stroke (Osuga et al. 2000) and, moreover, occurring as part of neurodegenerative processes.

Preservation of Genomic Integrity

RB is also crucial for preserving an intact genome, and, conversely, the dysfunction of RB is associated with aneuploidy (Hernando et al. 2004) which in turn may ultimately lead to cancer and other diseases. Conducive toward fulfilling this key function are the facts that RB is mainly a nuclear protein (Lee et al. 1987b) and, moreover, that RB (in its hyper-phosphorylated form) is able to directly bind to DNA (Wang et al. 1990).

Convergence Point for Various Other Inter- and Intracellular Signaling Antiproliferative Molecules as well as for Environmental Growth-Inhibitory Substances

It is important to emphasize that RB is the final common effector for various antiproliferative molecules that are
  1. (a)

    Part of the body’s own signaling network, such as p53 (Sherr 1996; Harrington et al. 1998; Brugarolas et al. 1999; Radulescu 2015) and zinc ions (Fong et al. 2000; Costello and Franklin 2012)

  2. (b)

    Of environmental origin, such as substances found in the bark of the lapacho tree (Choi et al. 2003); individual molecules within bee propolis (Kuo et al. 2006); quercetin, a flavonoid present in apples (Michaud-Levesque et al. 2012); sulforaphane which is a constituent of broccoli (Wang et al. 2004); ginger-derived substances (Park et al. 2006); as well as compounds contained in ginseng (Oh et al. 1999)


Summary: Protection of Life and Its Associated Promotion of Biodiversity

Taken together, RB preserves life by virtue of its various functions, more precisely not only due to those outlined above but also as a result of its promotion of hematopoiesis and neurogenesis during embryonic development (Lee et al. 1992). In addition, the fact that RB physically interacts with many different proteins has led investigators to compare it to a corral (Lee et al. 1994b) or, respectively, to a planet (Radulescu 2007). Thus, similar to marine corrals, RB likely contributes to(molecular)biodiversity (i.e., the “pluralism” of the biosphere) which in turn has been recognized as an important characteristic and consequence of life and its many specific molecular processes (Bishop 2003). For instance, the nuclear complex formation between RB and insulin (Radulescu et al. 2000; Radulescu 2015) expands in a symbiotic manner the diversity of metabolic and growth-regulatory signal transduction involving these two crucial proteins, besides the signaling cascades generated by insulin’s physical interaction with its cell membrane receptor in the extracellular space. Moreover, RB’s potential for oxygen binding (Radulescu 2007) putatively adds RB to the array of proteins transporting and/or storing oxygen as well as influencing redox processes, besides hemoglobin, myoglobin, and neuroglobin. Therefore, further interdisciplinary studies into these central functions of RB – not only as part of molecular medicine including bioinformatics (Takemura 2005), i.e., the biological counterpart of the similar fields of linguistics and epigraphy, but also extending into botany, marine biology, and biospeleology (Sarbu et al. 1996) – should be conducted as they might yield novel insights into this particularly versatile guardian of life, with conceivably interesting practical applications and also of possibly considerable relevance for ensuring the healthy survival of various species including of mankind in the upcoming years.


  1. Antelman D, Machemer T, Huyghe BG, Shepard HM, Maneval D, Johnson DE. Inhibition of tumor cell proliferation in vitro and in vivo by exogenous p110RB, the retinoblastoma tumor suppressor protein. Oncogene. 1995;10:697–704.PubMedGoogle Scholar
  2. Bishop JM. How to win the Nobel prize – an unexpected life in science. Cambridge: Harvard University Press; 2003. p. 229.Google Scholar
  3. Bookstein R, Shew JY, Chen PL, Scully P, Lee WH. Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science. 1990;247:712–5.PubMedCrossRefGoogle Scholar
  4. Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. Proc Natl Acad Sci U S A. 1999;96:1002–7.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature. 1983;305:779–84.PubMedCrossRefGoogle Scholar
  6. Chen PL, Scully P, Shew JY, Wang JY, Lee WH. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell. 1989;58:1193–8.PubMedCrossRefGoogle Scholar
  7. Choi YH, Kang HS, Yoo MA. Suppression of human prostate cancer cell growth by beta-lapachone via down-regulation of pRB phosphorylation and induction of Cdk inhibitor p21(WAF1/CIP1). J Biochem Mol Biol. 2003;36:223–9.PubMedGoogle Scholar
  8. Costello LC, Franklin RB. Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity. Expert Rev Anticancer Ther. 2012;12:121–8.PubMedPubMedCentralCrossRefGoogle Scholar
  9. DeCaprio JA, Ludlow JW, Lynch D, Furukawa Y, Griffin J, Piwnica-Worms H, Huang CM, Livingston DM. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell. 1989;58:1085–95.PubMedCrossRefGoogle Scholar
  10. Dyson N, Howley PM, Münger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989;243:934–7.PubMedCrossRefGoogle Scholar
  11. Fong LY, Nguyen VT, Farber JL, Huebner K, Magee PN. Early deregulation of the p16ink4a-cyclin D1/cyclin-dependent kinase 4-retinoblastoma pathway in cell proliferation-driven esophageal tumorigenesis in zinc-deficient rats. Cancer Res. 2000;60:4589–95.PubMedGoogle Scholar
  12. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643–6.PubMedCrossRefGoogle Scholar
  13. Harrington EA, Bruce JL, Harlow E, Dyson N. pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc Natl Acad Sci U S A. 1998;95:11945–50.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Hernando E, Nahlé Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M, Michel L, Mittal V, Gerald W, Benezra R, Lowe SW, Cordon-Cardo C. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature. 2004;430:797–802.PubMedCrossRefGoogle Scholar
  15. Kaye FJ. RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. Oncogene. 2002;21:6908–14.PubMedCrossRefGoogle Scholar
  16. Kuo HC, Kuo WH, Lee YJ, Lin WL, Chou FP, Tseng TH. Inhibitory effect of caffeic acid phenethyl ester on the growth of C6 glioma cells in vitro and in vivo. Cancer Lett. 2006;234:199–208.PubMedCrossRefGoogle Scholar
  17. Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987a;235:1394–9.PubMedCrossRefGoogle Scholar
  18. Lee WH, Shew JY, Hong FD, Sery TW, Donoso LA, Young LJ, Bookstein R, Lee EY. The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity. Nature. 1987b;329:642–5.PubMedCrossRefGoogle Scholar
  19. Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 1992;359:288–94.PubMedCrossRefGoogle Scholar
  20. Lee EY, Hu N, Yuan SS, Cox LA, Bradley A, Lee WH, Herrup K. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 1994a;8:2008–21.PubMedCrossRefGoogle Scholar
  21. Lee WH, Xu Y, Hong F, Durfee T, Mancini MA, Ueng YC, Chen PL, Riley D. The corral hypothesis: a novel regulatory mode for retinoblastoma protein function. Cold Spring Harb Symp Quant Biol. 1994b;59:97–107.PubMedCrossRefGoogle Scholar
  22. Michaud-Levesque J, Bousquet-Gagnon N, Béliveau R. Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration. Exp Cell Res. 2012;318:925–35.PubMedCrossRefGoogle Scholar
  23. Oh M, Choi YH, Choi S, Chung H, Kim K, Kim SI, Kim DK, Kim ND. Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells. Int J Oncol. 1999;14:869–75.PubMedGoogle Scholar
  24. Osuga H, Osuga S, Wang F, Fetni R, Hogan MJ, Slack RS, Hakim AM, Ikeda JE, Park DS. Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci U S A. 2000;97:10254–9.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Park YJ, Wen J, Bang S, Park SW, Song SY. [6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells. Yonsei Med J. 2006;47:688–97.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Radulescu RT. Planet RB: a personal contribution to a proteomic map of human retinoblastoma protein. 2007;arXiv:0706.1996.Google Scholar
  27. Radulescu RT. Going beyond the genetic view of cancer. Proc Natl Acad Sci U S A. 2008;105:E12.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Radulescu RT. From the RB tumor suppressor to MCR peptides. Protein Pept Lett. 2014;21:589–92.PubMedCrossRefGoogle Scholar
  29. Radulescu RT. The nucleocrine pathway comes of age. Romanian J Morphol Embryol. 2015;56(2):343–8. PMID: 26193197. https://www.ncbi.nlm.nih.gov/pubmed/26193197?dopt=AbstractPlus
  30. Radulescu RT, Fahraeus R. Targeting the RB pathway for cancer therapy: peptide mimetic foundations and promise. Am J Transl Res. 2010;2:209.PubMedPubMedCentralGoogle Scholar
  31. Radulescu RT, Jaques G. Selective inhibition of human lung cancer cell growth by peptides derived from retinoblastoma protein. Biochem Biophys Res Commun. 2000;267:71–6.PubMedCrossRefGoogle Scholar
  32. Radulescu RT, Jaques G. Potent in vivo antineoplastic activity of MCR peptides MCR-4 and MCR-14 against chemotherapy-resistant human small cell lung cancer. Drugs Exp Clin Res. 2003;29:69–74.PubMedGoogle Scholar
  33. Radulescu RT, Doklea E, Kehe K, Mückter H. Nuclear colocalization and complex formation of insulin with retinoblastoma protein in HepG2 human hepatoma cells. J Endocrinol. 2000;166:R1–4.PubMedCrossRefGoogle Scholar
  34. Sarbu SM, Kane TC, Kinkle BK. A chemoautotrophically based cave ecosystem. Science. 1996;272:1953–5.PubMedCrossRefGoogle Scholar
  35. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE, Herman JG. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57:3126–30.PubMedGoogle Scholar
  36. Sherr CJ. Cancer cell cycles. Science. 1996;274:1672–7.PubMedCrossRefGoogle Scholar
  37. Slack RS, El-Bizri H, Wong J, Belliveau DJ, Miller FD. A critical temporal requirement for the retinoblastoma protein family during neuronal determination. J Cell Biol. 1998;140:1497–509.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Takemura M. Evolutionary history of the retinoblastoma gene from archaea to eukarya. Biosystems. 2005;82:266–72.PubMedCrossRefGoogle Scholar
  39. Thomas L. The youngest science – notes of a medicine-watcher. New York: Bantam Books; 1983. p. 202–3.Google Scholar
  40. Wang NP, Chen PL, Huang S, Donoso LA, Lee WH, Lee EY. DNA-binding activity of retinoblastoma protein is intrinsic to its carboxyl-terminal region. Cell Growth Differ. 1990;1:233–9.PubMedGoogle Scholar
  41. Wang L, Liu D, Ahmed T, Chung FL, Conaway C, Chiao JW. Targeting cell cycle machinery as a molecular mechanism of sulforaphane in prostate cancer prevention. Int J Oncol. 2004;24:187–92.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Molecular Concepts Research (MCR)MünsterGermany