Retinoblastoma Tumor Suppressor Protein (RB)
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
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
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.
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