Cyanobacterial lipopolysaccharides and human health – a review

Cyanobacterial lipopolysaccharide/s (LPS) are frequently cited in the cyanobacteria literature as toxins responsible for a variety of heath effects in humans, from skin rashes to gastrointestinal, respiratory and allergic reactions. The attribution of toxic properties to cyanobacterial LPS dates from the 1970s, when it was thought that lipid A, the toxic moiety of LPS, was structurally and functionally conserved across all Gram-negative bacteria. However, more recent research has shown that this is not the case, and lipid A structures are now known to be very different, expressing properties ranging from LPS agonists, through weak endotoxicity to LPS antagonists. Although cyanobacterial LPS is widely cited as a putative toxin, most of the small number of formal research reports describe cyanobacterial LPS as weakly toxic compared to LPS from the Enterobacteriaceae. We systematically reviewed the literature on cyanobacterial LPS, and also examined the much lager body of literature relating to heterotrophic bacterial LPS and the atypical lipid A structures of some photosynthetic bacteria. While the literature on the biological activity of heterotrophic bacterial LPS is overwhelmingly large and therefore difficult to review for the purposes of exclusion, we were unable to find a convincing body of evidence to suggest that heterotrophic bacterial LPS, in the absence of other virulence factors, is responsible for acute gastrointestinal, dermatological or allergic reactions via natural exposure routes in humans. There is a danger that initial speculation about cyanobacterial LPS may evolve into orthodoxy without basis in research findings. No cyanobacterial lipid A structures have been described and published to date, so a recommendation is made that cyanobacteriologists should not continue to attribute such a diverse range of clinical symptoms to cyanobacterial LPS without research confirmation

Dispersion of the ras Family of Transforming Genes to Four Different Chromosomes in Man

Cellular transforming genes (c-onc) are evolutionarily conserved vertebrate DNA segments which have been identified by two different approaches. One group of these cellular genes has been defined by their close homology to the transforming genes of the acute transforming retroviruses (v-onc). The second group, which represent activated forms of normal cellular genes, has been detected by the ability of certain genes from animal and human tumours to induce focal transformation of tissue culture cells. Investigation of the possibility that the same cellular gene might have given rise to both a retroviral and a tumour transforming gene revealed that two of the c-onc genes identified by transfecting genomic DNA from human tumours to murine 3T3 fibroblasts were related to the transforming genes of two closely related acute transforming retroviruses, Harvey murine sarcoma virus (HaMuSV) and Kirsten murine sarcoma virus (KiMuSV). The transforming genes of HaMuSV and KiMuSV are derived from two members of a cellular onc gene family called ras, which is a rather divergent group of normal vertebrate genes originally found by analysis of the cellular homologues of the v-onc genes of HaMuSV and KiMuSV. Four distinct human cellular homologues of v-Ha-ras and v-Ki-ras (designated c-Ha-ras and c-Ki-ras, respectively) have been characterized; two (c-Ha-ras-1 and c-Ha-ras-2) are more closely related to v-Ha-ras, while the others (c-Ki-ras-1 and c-Ki-ras-2) are more closely related to v-Ki-ras. On ligation with a retroviral long terminal repeat, the c-Ha-ras-1 gene of both rat and human have been shown to induce in vitro transformation of mouse NIH 3T3 cells by DNA transfection. This gene and c-Ki-ras-2 have also been isolated as activated transforming genes in human tumours. An understanding of the genetic relationship of the c-ras genes and additional genetic loci possibly involved in neoplastic transformation would be greatly facilitated by placement of the ras genes on the human chromosome map. Using DNA analysis of rodent×human somatic cell hybrids, we have now assigned each of the human genes to a different chromosome

Loss of protein phosphatase 2A regulatory subunit B56δ promotes spontaneous tumorigenesis in vivo.

Protein Phosphatase 2A (PP2A) enzymes counteract diverse kinase-driven oncogenic pathways and their function is frequently impaired in cancer. PP2A inhibition is indispensable for full transformation of human cells, but whether loss of PP2A is sufficient for tumorigenesis in vivo has remained elusive. Here, we describe spontaneous tumor development in knockout mice for Ppp2r5d, encoding the PP2A regulatory B56δ subunit. Several primary tumors were observed, most commonly, hematologic malignancies and hepatocellular carcinomas (HCCs). Targeted immunoblot and immunohistochemistry analysis of the HCCs revealed heterogeneous activation of diverse oncogenic pathways known to be suppressed by PP2A-B56. RNA sequencing analysis unveiled, however, a common role for oncogenic c-Myc activation in the HCCs, independently underscored by c-Myc Ser62 hyperphosphorylation. Upstream of c-Myc, GSK-3β Ser9 hyperphosphorylation occurred both in the HCCs and non-cancerous B56δ-null livers. Thus, uncontrolled c-Myc activity due to B56δ-driven GSK-3β inactivation is the likely tumor predisposing factor. Our data provide the first compelling mouse genetics evidence sustaining the tumor suppressive activity of a single PP2A holoenzyme, constituting the final missing incentive for full clinical development of PP2A as cancer biomarker and therapy target.Oncogene advance online publication, 2 October 2017; doi:10.1038/onc.2017.350