Review Article the CELL SURVIVAL PATHWAYS of the PRIMORDIAL
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European Journal of Microbiology and Immunology 5 (2015) 1, pp. 25–43 Review article DOI: 10.1556/EuJMI-D-14-00034 THE CELL SURVIVAL PATHWAYS OF THE PRIMORDIAL RNA–DNA COMPLEX REMAIN CONSERVED IN THE EXTANT GENOMES AND MAY FUNCTION AS PROTO-ONCOGENES Joseph G. Sinkovics* St. Joseph’s Hospital Cancer Institute Affiliated with the H. L. Moffitt Comprehensive Cancer Center, Morsani College of Medicine, Department of Molecular Medicine, The University of South Florida, Tampa, FL, USA Received: December 2, 2014; Accepted: December 22, 2014 Malignantly transformed (cancer) cells of multicellular hosts, including human cells, operate activated biochemical pathways that recognizably derived from unicellular ancestors. The descendant heat shock proteins of thermophile archaea now chaperon oncoproteins. The ABC cassettes of toxin-producer zooxantella Symbiodinia algae pump out the cytoplasmic toxin molecules; malignantly transformed cells utilize the derivatives of these cassettes to get rid of chemotherapeuticals. High mobility group helix– loop–helix proteins, protein arginine methyltransferases, proliferating cell nuclear antigens, and Ki-67 nuclear proteins, that protect and repair DNA in unicellular life forms, support oncogenes in transformed cells. The cell survival pathways of Wnt–β-catenin, Hedgehog, PI3K, MAPK–ERK, STAT, Ets, JAK, Pak, Myb, achaete scute, circadian rhythms, Bruton kinase and others, which are physiological in uni- and early multicellular eukaryotic life forms, are constitutively encoded in complex oncogenic pathways in selected single cells of advanced multicellular eukaryotic hosts. Oncogenes and oncoproteins in advanced multicellular hosts recreate selected independently living and immortalized unicellular life forms, which are similar to extinct and extant protists. These uni cellular life forms are recognized at the clinics as autologous “cancer cells”. Keywords: Caenorhabditis, cell survival pathways, ctenophores, de-differentiation, Drosophila, early multicellular eukaryotes, exosomes, malignant transformation, proto-oncogenes/oncogenes, reversed ontogenesis, tumor immunology, unicellular eukaryotes Introduction vated beginning with anti-apoptotic features, and followed by the loss of inhibitory factors of the cell cycle. The me- The presence and the molecular chemistry of essential on- tabolism of these cells continues without senescence and togenetic and life-sustaining biological systems, the “cell natural death. Genomic and proteomic studies indicate that survival pathways,” were compared in extant uni- and ear- the biochemical pathways operational in these life forms ly multicellular organisms with those of evolutionarily ad- are derivatives of their ancient ancestors’ ontogenetic and vanced multicellular subjects, including vertebrate mam- cell survival pathways. Characteristically, upon external malians, in particular Homo. The presumption that the interventions, a blocked pathway is readily replaced by basic molecular biology of extant organisms was acquired another activated pathway. In a multicellular host, these and inherited from extinct and extant predecessors was ac- unicellular life forms subvert the host’s immune reactions cepted. The natural occurrence of genome duplications and and induce host cells to provide growth factors to them. thus new gene formations, as well as gene losses, were tak- In addition to their major replicatory pathways often en into account. It was recognized that organisms evolving constitutively expressed, these life forms carry large num- from ancestral-to-extant entities have operated these mo- bers of different single point-mutations that could enable lecular biological pathways for hundreds of million years. one of them to live and metabolize in almost any physico- The extant genomes exhibit a faculty for transformation of chemical environment. In the clinics, these life forms are mature cells into those of unicellular life forms, which are recognized as autologous cancer cells and the malady of characterized by incessant replication and extraordinary cancer is diagnosed. These interactions between host and resistance to physicochemical insults. These biochemical its own parasitic life forms often result in the consump- reactions in these life forms appear to be sequentially acti- tion and death of the multicellular host. The clinics design * Corresponding author: Joseph G. Sinkovics; Cancer Institute, St. Joseph’s Hospital, 3001 Dr. Martin Luther King Jr. Blvd., Tampa, FL 33607-6307, USA; Phone: 813-870-4255; Fax: 813-870-4825; E-mail: [email protected] ISSN 2062-509X / $ 20.00 © The Author Unauthenticated | Downloaded 09/29/21 04:12 PM UTC 26 J. G. Sinkovics treatment protocols for the elimination of cancer cells, The GSK-3 (glycogen synthase kinase) protein interacts possibly without harm to the host (not yet achieved). The with cytoplasmic β-catenin. Accumulating cytoplasmic biologists view the phenomena of cancer as manifestations β-catenin eventually enters the nucleus, where it is direct- of an inherent faculty in the RNA–DNA genome for the ed to the ancestral tcf gene (T cell factor) DNA. The tcf sustenance of cellular life in the universe through inex- DNA expresses β-catenin-binding domains, and when so haustible mutability and the reversal of ontogeny/phylog- activated, it encodes protein TCF. This interaction occurs eny in these subjects (referenced in [1]). only in mesoderm-precursor cells. β-Catenin performs two sequential binary fate switches for the separation of ecto- derm and mesoendoderm, and mesoderm and endoderm. Unicellular and early multicellular The ectodermally destined precursor cells express ephrin. eukaryotes express their cell survival By the 32-cell stage, the embryo has separated its ectoder- pathways. Selected single cells of a mal, mesodermal, and endodermal lineages [2]. Prominent other genes cooperating are those of the FGF–MAPK–Ets multicellular host express the derivatives pathways [3], all becoming proto-oncogenes in mamma- of these systems as proto-oncogenes lian vertebrate genomes. The fi rst mammalian wnt gene was discovered by R. Several ontogenetic and vital molecular biological path- Nusse and H. Varmus [4] in breast cancer-susceptible and ways are operational and shared in unicellular eukaryota MMTV-carrier (mouse mammary tumor virus, Bittner) (amoeba, including Dictyostelia), giardia, trichomonas, mice. However, the MMTV genome possessed no recog- choanofl agellates, ciliates and paramecia, kinetoplastids nizable oncogene in opposition to other retro- and reticulo- (the Trypanosoma), the fungus Neurospora crassa, and endotheliosis viruses, which incorporated various growth the oomyceta Phythophthora infestans. The genomes of factor genes of their host cells, led by the Rous sarcoma the fi rst multicellular organisms, the urochordate tuni- retrovirus. Instead, MMTV inserted the DNA copy of cate Ciona; the Cnidaria, prominently including the sea its RNA genome into one particular gene of its host cell anemone Nematostella vectensis, Hydra, Hydractinia, and (gene int-1, for integration). Gene int-1, by itself, without Medusozoa; the Spongiae; the Strongylocentrotus sea ur- MMTV gene insertion, proved to be oncogenic in mice chins; and the protochordate Branchiostoma fl oridae, the (inducing breast cancers). Gene int-1 turned out to be the representative of the amphioxus clade, conserved these mammalian homolog of the drosophila gene wingless, so systems. The most prominent ontogenetic and cell survival the human int-1 and int-2 genes are mapped to chromo- pathways commonly shared by these entities are those of somes 12q14 and 11q13 [5, 6]. the Wnt–β-catenin circuitry resulting in the intranuclear For distinction, the fi rst int-1 gene was renamed wing- activation of the ancestral tcfTCF/lefLEF genes and gene less-related integration site, “wnt/Wnt.” In the meantime, product proteins. Their antagonists are the dickkopf (dro- the vertebrate Wnt family grew to 19 members. sophila) gene product proteins. Their collaborators are the The drosophila protein Armadillo is the homolog of Hedgehog Hh, PI3K, MAPK–ERK, Ets, and JAK–STAT β-catenin; the drosophila homolog of GSK is zeste, and pathways (wingless/integrated, T cell factor/lymphocyte Wnt is a GSK3 antagonist (and vice versa). Healthy GSK enhancer factor, phosphatidyl inositol kinase, mitogen- phosphorylates β-catenin at serine/threonine residues, activated protein kinase, extracellular regulated kinase, thus, marking it for degradation by ubiquitination. Elimi- retrovirus E26, Janus kinase, signal transduction, and ac- nation of its phosphorylation sites stabilizes β-catenin. tivation of transcription). Further, frequently shared cell Within the healthy GSK, APC (adenomatous polyposis survival genes are those of the heat shock proteins (HSP), coli), and Axin (homologous to Disheveled) complex, insulin-like growth factors (IGF), tumor necrosis factor β-catenin is destroyed. Frizzled transmembrane proteins (TNFα), transforming growth factors (TGFαβ), (decapen- signal Disheveled. Homologs of the drosophila protein taplegic, drosophila), and their antagonists, and the infl am- Arrow, the LRPs (low density lipoprotein receptor-related matory oncoprotein, nuclear factor kappa B (NFкB) [1]. proteins), are positioned adjacent to Frizzleds in the cell Many proto-oncogenes were discovered in advanced membrane. Their phosphorylated cytoplasmic tail inter- multicellular organisms. When rediscovered in unicellu- acts with the GSK3–Axin complex. When β-catenin es- lar eukaryotes,