Page 19 - Winter2018

called nucleoporins, one of which is Nup98. In addition, lymphoma cells often have constitutively active versions
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Importantly, when Nup98 gets heavily phos- of NF-κB, which helps to keep the phosphorylation cascade going in a
phorylated, it breaks apart from its partners in runaway fashion. Both the AID and the NF-κB also stick around in the
the pore and the gel disintegrates, leaving the nucleus rather than getting escorted back out to the cytoplasm. NF-κB
pore wide open such that both AID and NF-κB launches a runaway phosphorylation cascade that causes both rogue
can now freely enter the nucleus. proteins to gain free access to the nucleus because of hyperphosphoryla-
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In addition to the proteins that tether AID tion of Nup98, and AID has a field day in the nucleus, mutating genes
and NF-κB in the cytoplasm, there are also right and left and stripping off methyl groups until the cell turns into a
specialized escort proteins called importins that pluripotent cancer stem cell (that is, a lymphoma cell).
can bind to AID or NF-κB and hand-carry them
across the gelled pores right into the nucleus. EXCESSIVE PHOSPHORYLATION
These proteins are only able to work under the AND ALTERED DNA METHYLATION
special conditions that follow the signaling that How does a phosphorylation cascade get started? One common
alerted the B cell of the marauding viral attack. way is through excessive calcium uptake by the cell, which can trigger
Other proteins hand-carry them back out of the NF-κB expression and subsequent phosphorylation cascades, mutagenesis
nucleus once their job is done, because it’s too and tumorigenic proliferation. Calcium uptake is an early response of
dangerous to let them continue their nuclear B cells following exposure to antigen. Glyphosate has been found to
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activities over an extended period of time. induce excessive calcium uptake in both in vitro and in vivo experiments
However, if Nup98 is heavily phosphorylated, in multiple cell types: Sertoli cells in the testes, neurons and cardiac
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these escort proteins are no longer necessary muscle cells.
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because AID and NF-κB can now enter or leave NF-κB is a powerful signaling molecule that induces expression of a
the nucleus any time they want. In particular, large number of proteins associated with cell survival and proliferation,
they can get in the nucleus and then become including many kinases. It is activated in response to tumor necrosis factor
bound to the nuclear DNA and continue their alpha (TNF-α) signaling, which, in turn, is induced by multiple cellular
unchecked activities with abandon. stressors. As previously discussed, NF-κB is secured in the cytoplasm by
Studies have shown that AID plays an es- inhibitor κB (IκB), and its release is dependent on expression of a kinase
sential role in the development of B-cell lym- that phosphorylates IκB.
phomas. Non-Hodgkin’s lymphoma cells are The cytokines interleukin 1 beta (IL-1β) and TNF-α are commonly
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very peculiar. First of all, they express AID expressed under stress conditions, and studies have shown that they are
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at a very high level, and the AID tends to hang upregulated in tissues following glyphosate exposure. 43,44 A study on
out in the nucleus rather than in the cytoplasm carp exposure to glyphosate showed increased expression of TNF-α in
where it is normally sequestered. Secondly, liver, kidneys and spleen. TNF-α, IL-1β and NF-κB expression levels
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their AID proteins are highly phosphorylated, were all significantly increased in the livers of rats exposed to glyphosate
and phosphorylation changes AID’s behavior at fifty mg/kg daily for thirty-five days. Experiments have shown that
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in shocking ways, such that it starts putting these cytokines tend to stimulate calcium uptake by various cell types.
mutations into lots of other proteins besides the TNF-α induces calcium uptake in vascular smooth muscle cells, and
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immunoglobulins. As a result, many so-called it also induces NF-κB expression in neurons. IL-1β has been shown to
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“oncogenes” (genes that can transform a cell induce calcium uptake in pancreatic islets.
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into a tumor cell) are hypermutated in associa- Glyphosate causes excitotoxicity in neurons through excessive
tion with B-cell lymphomas. AID also strips stimulation of the N-methyl-D-aspartate (NMDA) receptors in the hip-
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the cell’s DNA of its methyl groups; this is im- pocampus, leading to excessive calcium uptake. It is well established
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portant because a cell with demethylated DNA that calcium uptake in hippocampal neurons induces expression of NF-
will revert to a pluripotent stem-cell-like form κB. Glyphosate activates voltage-dependent calcium channels, in part
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where it refuses to differentiate and just keeps by acting as a glycine analogue at the receptor site for glycine, and it
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on cloning itself endlessly—that is, it becomes also activates the serine-threonine kinase protein, calmodulin-dependent
a tumor cell. Non-Hodgkin’s lymphoma cells protein kinase II (CaMKII). This in turn launches a flurry of activities
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also often have rogue versions of kinases that are that ultimately result in hyperphosphorylation of a large number of pro-
“constitutively” expressed, meaning that they teins in the cell.
just keep on phosphorylating other proteins in Glyphosate also has been shown to induce alterations in methylation
an out-of-control fashion. 38 patterns in the genome that are consistent with progression toward cancer.

WINTER 2018 Wise Traditions 17