Showing posts with label dna replication. Show all posts
Showing posts with label dna replication. Show all posts

Saturday, March 30, 2013


A living cell is in constant motion. At any given time, there are periods of chemical reactions unfolding in a living cell. These processes are occurring 24/7. Despite their large number, they are not random, but are coordinated and purposeful. They have one overall objective which is the survival of the cell against all odds. However, when they cannot preserve life, they initiate the programmed cellular death. 
These cellular reactions respect basic chemical laws of ion and atom interactions. However, the general direction from reactions is imposed by the cellular mission which is clearly determined by the location of the cell in a tissue or organ and the expected function to be performed by the organ. At any given point in time, the cell is either in differentiation or proliferation, or changing to adapt to current circumstances of the cell. These functions and adaptations are caused by environmental stimuli reaching the cell.
 These stimuli could be chemical, hormonal, traumatic or electric and they reach receptors which cross the cellular boundaries or membrane, and affect the molecules belonging to a signal transduction pathway. The signal goes on to affect genes in the nucleus of the cell where DNA will be replicated to achieve or respond to the stimuli accordingly. All reactions follow a certain flow to achieve a purpose for the cell. To control the general direction of reaction the cell uses several methods: the first is to silence un-needed genes and to amplify the expression of needed genes that carry the code for the mission to be performed. 
The cell will enter division and proliferation of those genes to impose the general direction or flow of the reaction. The second method used to impose the general direction is the formation of genes that can catalyze or force the reaction to go a certain way: these are called "enzymes" for that particular reaction. If an enzyme is not formed, the reaction is not allowed to progress. Therefore, the control of what is happening is occurring this way. A third way to control the flow of direction is to promote proteins called "regulators". The more the regulators in a reaction, the more likely that regulated reaction can occur in a controlled fashion. The fourth way of controlling reaction is mole fraction which puts together certain regulators and enzymes or proteins in general which are aligned in a chain and forces molecules to go from one protein to another in the mole in a certain direction so that the output is what is needed for the mission. 
These mole-like complexes of proteins are called "core binding factors". Any protein function not needed will not be incorporated in the complex. Genes are silenced by methylation, or simply by being attached to patches of molecules that belong to the histones, the histones that cover genetic material. At any given point, when a gene is needed, the cover can be re-opened or pulled back, which is called "gene remodeling". A cancer cell will tend to move away from the location where it is located not because of its intention to kill the host, but because in that location the nutrients and local conditions will be inadequate eventually to allow further growth. It will seek another location to survive. Before it moves away, it has to take steps to protect its survival. It will break adhesion to surrounding cells; this is mostly achieved by decreasing its surface adhesion molecules. It will secrete proteins that can break fibers on its way in order to get through and detection of these proteins called “metalloproteases” can signal doctors that the disease, the cancer, is on the move. In certain circumstances, it produces a mucus to protect itself against detection by the immune system. 
When it arrives in the new location, the cell will produce a hormone or growth factor which gives itself advantage over the already present cells in that location. This is generally called a “tumor growth factor”. The potential for proliferation, division and growth advantage is driven through the signal transduction pathway inside the cell. This is generally achieved by the expression of a driver gene which is amplified or over-expressed forcing reaction for downstream pathways. This is called a “driver mutation”. 
Experience with chemotherapy which was like a bomb with an indiscriminate effect affecting both good and bad cells of the host has only been able to achieve 20 to 30% of cure. Today, scientists are targeting the driver mutations to stop pathways of growth of cancer cells. We are now getting higher response rates and starting to see response in cancers that were resistant to chemotherapy, e.g. melanoma. People used to talk about cure without believing in their own statement, but with the advance of target therapy, cure is a real possibility. We are just at the beginning of our understanding of the various targets. Cure will be achieved.

Saturday, February 16, 2013


There is increasing evidence that Cyclins are integrins and so are Tumor growth factors, Tumor Necrosis factors, interleukins and interferons.
All these are membrane proteins with a particularity to be released from Metalloprotease and related adhesion molecules depending on the nature of stimuli.  The discovery and description of ADAMs as type I membrane protein containing Metalloproteinase and an integrin domain locate the growth factors and Cyclins squarely at the membrane  (surface and reticulum membrane).  These proteins, once released, go straight to the Nucleus to unveil their might by activating transcription factor.  In their track to the nucleus they can amplify and activate signal transduction pathways as well as either molecules. The cyclins find cytoplasmic and protein substrates (mostly enzymes)  which have their specific domains and link to the site to activate them most of the time, changing their shapes so as to expose hidden electrons or atomic groups (such SH) to cause downstream chain activation.

Now as the pathway unfolds at light speed (or electronic speed) it may overwhelm the cell, protection has to be assured to hide death domains (which also are integrins and therefore at the membrane) and pathways to Apoptosis.  Protection at the membrane seems to be offered by the INK while the CIP/Kip.  But deep in the cell are the Bcl-like proteins. The CIP/Kip seems to work like Decoy specific proteins since the have Cyclin domain to stop them from stimulating their respective CDKs (Cyclin dependent Kinases).  Some CDKs need 2 or more different stimulations to accomplish their deed. And with the number of stimulations comes the consequent activation of various substrates.  The Retinoblastoma substrate governs the G1 progression phase in the cell cycle, but it needs at least 2 activations, first by Cyclin D followed by activation by Cyclin E in order for it to free E2F that light up tarnscrptions genes which control the path to S-phase.  This Cyclin E also activates processes leading to Histone Biosynthesis, Centrosome activity and DNA replication.  And in fact, Cyclin E is the one that leads to gene instability that characterize many triple negative breast cancers


One of the CIP/Kip(s) is the P21 which plays a role in the cell cycle arrest due to P53 activation.
I should note that the Kinase itself may be mutated.  CDK4 is mutated in Melanoma, it renders the INK4 protein unable to occupy its domain and therefore is free to affect the nuclear transcription factor.  Therefore the solution is to increase the ligand to INK4 so as to increase its ubiquitination and and degradation through the proteasome (Ipilimumab/CTLA 4 in T cell/ does not do this unfortunately, so there is more room for you to research).  YES, LIKE FOR MERCEDES, WE NEED THE E CLASS OF PROTEINS TO FURTHER UBIQUITINATION.  A MUTATION IN E CLASS (WHICH INCLUDES MDM2) WILL BE BAD IN MELANOMA!

Suffice is to show that what starts at the membrane moves quickly to the nucleus in a milli-milli second in a flash and turn the life of the host around!

It is worth noting that not only Cyclins can be blocked from entering the Nucleus where they trigger transcription factor formation, but sometimes the Decoy (Cip/Kip) is stopped from entering the nucleus and cannot stop Cyclins which have entered the nucleus: this happens in breast cancer (p27 mislocation)