NFkB ~ The Myopic Salesman

I came across this story in which several people got hurt. All of them belonged to disparate families and in different regions. The calamity wrought upon each community was immeasurable. Several squads of police cars and CSI units were dispatched to find out what happened in each locality. Yet the mystery continued.

Distraught from the pain and suffering, a young girl, while reading a newspaper realized that the events at the other places seemed to match in some respect the one that had ravaged her community. Taking the thread, she began to sow the fabric of the mystery and eventually found out the culprit; a quiet, myopic, unassuming but well dressed salesman who had keys to the hearts of willing and gullible individuals.

And it made me think of NFkB

You should right about now give a hooting laughter. What did he say?

Yup! I stand by it and here is how.

25 years ago, David Baltimore and Ranjan Sen discovered this DNA binding ubiquitous protein complex that has become the focus of our attention.

NFkB (or nuclear factor kappa-light-chain-promoter of B-cells), is a n interesting little fellow that resides in the cytoplasm of the cell. There it sits quietly as heterodimers, until provoked. Once provoked it phosphorylates and takes the shoots down into the nucleus. And that is where the climactic journey begins.

“NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis.

“All proteins of the NF-κB family share a Rel homology domain in their N-terminus. A subfamily of NF-κB proteins, including RelA, RelB, and c-Rel, have a transactivation domain in their C-termini. In contrast, the NF-κB1 and NF-κB2 proteins are synthesized as large precursors, undergoing processing to generate mature and active NF-κB subunits.

NF-κB is detected in most cell types, and specific NF-κB binding sites are identified in promoters and enhancers of increasing number of inducible genes. The transcription factor NF-κB consists of homo- or heterodimers of different subunits, members of a family of structurally related proteins – Rel / NF-κB proteins. Rel proteins contain a conserved N-terminal region, called the Rel Homology Domain (RHD), which contains the DNA-binding and dimerization domains and the nuclear localization signal of the Rel proteins.

NFkB exists in five forms within the cytoplasm and is bound exclusively to the Rel proteins, where they exist in quiet and peaceful harmony watching the daily chores of the cell go by. But, and here is the big but, if one of the invaders dares interfere with the cellular function and by that I mean, say a virus, bacterium, a foreign particle, lipopolysccharide, or even LDL float inside the cytoplasm through the cellular membrane that degrades the binding protein and releases the activated NFkB. Receptor activator of nuclear factor kappa B, which is a type of TNFR, is a central activator of NF-κB.

http://youtu.be/WgqAjYKjXAc

All hell breaks loose.

NF-κB can be activated by a number of stimuli, including exposure of cells to Lipopolysaccharides or inflammatory cytokines such as Tumor Necrosis Factor or Interleukin-1, growth factors, lymphokines, oxidants, free radicals, inhaled particles, viral infection or expression of certain viral or bacterial gene products. 

The first event of a loose NFkB (so to speak) is to acquire a phosphorous group which kicks it into motion (like an energy pill). Once the NFkB has been phosphorylated it rapidly activates it’s N and C-terminal groups for travel into the nucleus of the cell where it attaches itself to the DNA with its DNA binding site. It is like a hello with a shaking of the hands, transiently in some cases and in other cases the hand-shaking never ends, lke some relatives you want to avoid.

Let me get to those two phases:

Transient hand shaking occurs in most infectious and irritant causes. A virus attacks and the cell releases its NFkB to proceed down the hatch and bind to the DNA to promote the genes required for cellular response to create more immune cells against invader. Since NFkB is in the “Rapid Response Team” this is a “Fast and Furious” process.

In some cases the NFkB through its activation can bind selectively to the “inhibitor gene” that suppresses the cellular growth phenomenon also.

Why the disparity of action, you might ask?

The Growth Switch

Well, you see eons of evolution between the bugs and us humans has helped evolve different mechanisms of coexistence. Some, as in E Coli have tendency to suppress the NFkB in the Urinary tract so that the E Coli can continue to do its monkey-business. Equally the Epstein Barr Virus or EBV does the same suppression in order to cause infectious mononucleosis. These mechanisms are defined by the claiming of advantage for survival for the bug. We on the other hand without a remedy an antibiotic (in E Coli case) are at its mercy.

The Kill Switch

On the other hand, the EBV can play a two-faced-Janus type of a drama where it can instead of inhibiting, start promoting the cellular gene that causes proliferation and there in lies the tragedy of diseases like nasopharyngeal cancer and the real baddy, Burkitts Lymphoma caused by the EBV. You can see the deviousness of this salesmanship cant you? Come in to sell something and ransack the place instead.

Now let us look at the SWOT analysis of this tiny speck within the tiny speck.

NFkB                         Strengths:

1. It is Ubiquitous in nature and in all living cells.
2. It has a direct link to the DNA.
3. It can promote or regress a cellular response.
4. It helps against infections
5. It causes diseases including cancer with sustained activity on promoter genes.

          Weakness:

1. It is susceptible to intervention.

           Opportunities  

     1.   Through research, one can activate it to bind with the inhibitor gene as in cancer.

                                   Threats

     1.   Unintended Consequences within the cellular mechanism and framework

Any signal that presages the need for an immune or inflammatory response and both are closely related cousins, by the way, the NFkB has the answer. It gets activated (chatty) then transfers itself to the nucleus (runny) and binds to one of two signaling genes (friendly) on the grand double-helical loop of our existence called the DNA.

Our immunity is based on a cascade of events that occur. But for any of those events to be initiated, the culprit responsible is our very own, NFkB. It is needed for various functions including, monocyte adhesion, macrophage recruiting, platelet activation and smooth muscle contraction, all necessary components to save us from the dread of an allergen, virus, bacterium and even mold.

Several studies are in progress to quiet this little critter. After all unchecked, it can cause significant and unabated inflammation as in Ulcerative Colitis, Crohn’s Disease, Autoimmune disorders; like lupus, and of course the scourge of humanity, cancer itself. But in passing let me throw this soft toss at my cardiology friends. NFkB is intimately involved with the induced inflammation from the lipolysaccharides, and the VLDL, LDL that promote atherosclerosis. Understanding of course that something other, like a bacterium, eg. Chlamydia can provoke the initiating event in the coronary blood vessel that starts the heartache.

In other cancers it can stifle the immune network by not reacting to the wayward cancer cell and allow the disease to flourish. Or it can maintain the inflammatory response which by its own attributes can liberate other factors that can promote various receptors on cells surfaces to signal the nucleus to start proliferating and proceed to a malignancy.

Few of the many Pathways that dictate cellular Growth

There are many transcription factors housed within the cell and an activated NFkB can “touch” their “sensitivity” and activate them to release their signals into the nucleus for cellular growth too. Cancer itself is mainly a process with unchecked signaling of the promoter genes of cell proliferation. These promotional events within the cell can be checked if a strong enough barrier of suppressor genes are also cohabiting the nucleus and are active. That would be like sitting in a Ferrari and pressing both the accelerator and the brakes. Who wins, depends on, who blinks!

I hope you can see the blinding fury of a myopic salesman. Can"t you?

And of course we can devise an Anti NFkB antibody and check out its presence in cancers and other tissues for posterity.

Red colored cells indicate cancer with NFkB activation

The moral of this story is not to let the salesman in!

Keep the Inflammation Out!

Diet: Eat healthy; vegetables and fruits.

Exercise: in Moderation.

Stress: Limit ~ since it jogs the immune system too.

Wash hands frequently especially before eating ~ but do not get paranoid with Purells.

Remember: "Cleanliness is next to Godliness."

References:

Perkins ND (January 2007). "Integrating cell-signalling pathways with NF-κB and IKK function". Nat. Rev. Mol. Cell Biol. 8 (1): 49–62.

Ghosh S, May MJ, Kopp EB (1998). "NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses". Annu. Rev. Immunol. 16: 225–60.

Gilmore TD (1999). "The Rel/NF-κB signal transduction pathway: introduction". Oncogene 18 (49): 6842–4

Chandel NS, Trzyna WC, McClintock DS, Schumacker PT (July 2000). "Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin". J Immunol 165 (2): 1013–1021.

Gilmore TD (2006). "Introduction to NF-κB: players, pathways, perspectives". Oncogene 25 (51): 6680–4

Karin M, Ben-Neriah Y (2000). "Phosphorylation meets ubiquitination: the control of NF-κB activity". Annu. Rev. Immunol. 18: 621–63.

Hayden MS, West AP, Ghosh S (October 2006). "NF-κB and the immune response". Oncogene 25 (51): 6758–80