STRATIFIN (IN OVARIAN CANCER)

LAM et al.

 " Stratifin, also known as 14-3-3 sigma protein, stimulates matrix metalloproteinase (MMP)-1 expression in dermal fibroblasts.  Treatment of dermal fibroblasts with stratifin resulted in rapid and transient upregulation of c-jun and c-fos mRNA levels.  Stratifin was demonstrated to increase MMP-1 protein levels. Microarray analysis of stratifin-treated fibroblasts shows an increase in Elk4/Sap1 mRNA expression and this finding was confirmed by northern blot analysis. Our results indicate that stratifin markedly increase Elk4/Sap1 mRNA expression in a time-dependent fashion. In conclusion, stratifin stimulates fibroblast MMP-1 levels through the activation of c-fos and MAPK pathway."

Our interpretation is that stratifin is part of an intergrin, its release in the Cytoplasm indeed stimulate MAPK C-JUN and c-fos.  This means it is interpretated by the cell as a chemical stressor. The NF-kB is not far away.  One of the most important hidden information here is the note by the authors that there is an increase of ELK4/Sap1.

ELK4 has been shown to interact with Serum response factor^[4][5] and BRCA1.^[6]

Serum response factor has been shown to interact with NFYA,^[10] Src,^[11] CREB-binding protein,^[12] GTF2I,^[13][14] ATF6,^[15] Nuclear receptor co-repressor 2,^[16] CEBPB,^[17][18] GATA4,^[19][20] Myogenin,^[21][22] GTF2F1,^[23][24] TEAD1,^[25] ELK4,^[15][26] Promyelocytic leukemia protein^[12] and ASCC3.^[27]

(wikipedia)

(PLEASE, WHEN A MOLECULE INTERACT WITH THIS MANY MOLECULE, IT IS A PERFECT, LEGITIMATE TARGET FOR THERAPY, AND SFR DOES)

ELK4 therefore control BRCA1 and serum response factor which control NFYA.  This uncover what the cancer cell has to do to start the neoplastic process.  It has to derail genetic repair by abrogating the action of BRAC1, but it also has to take controles of CBF complexes  and NFYA and ZHXY.  Remember CBF complexes control the direction of the metabolism, In essence, when it comes to function in the cell,  the role of Core Binding Factors (CBF) is indistinguishable from that of TRANSCRIPTION FACTORS.  They all impose the direction that the cell metabolism should take.

Remember also that because the Stratifin engages the MAPK mostly through the certain well selected CDK, it will tend to stop cell division.  In Breast cancer, Stratifin is one of the earliest methylated gene slated for silencing.

CDO1:
 Cysteine dioxygenase type I, IS A GENE CONTROLLING  CYSTEIN METABOLISM. DEEP ANALYSIS BRINGS THIS GENE TO ELECTRON EXCHANGE FOR THE FORMATION OF CYTOCHROME C, THE WAY TO APOPTOSIS.  THE CANCER CELL QUICKLY METHYLATES THIS GENE EARLY AND MUTATION HAS BEEN LINKED TO PROGNOSIS
 (WORK FROM CORNELL UNIVERSITY)

TTP

THROMBOTIC THROMBOCYTOPENIC PURPURA (HYPOTHESIS CONTINUES)

Here is the example of a metastatic mechanism going bad when it hits the right ADAM.  Remember that ADAM are made of 2 basic domains, one an integrin and one a metalloproteinase domain.  The Metalloproteinase enters the Flippase-floppase (or sometimes scramblase)-like structure and is destined to be rejected outside, the Integrin is sent inside the cell.
Metalloproteinases are sent outside and attack collagen-like molecules to open the way to cell migration and allow Metastatic processes to move forward.  However, the cell membranes have a collagen-like structure, too.  So potentially the released Metalloproteinases could attack the cell.  The cell is not stupid and knows what metalloproteinase it has put out.  So it shields itself with Inhibitors and Decoy receptors from that specific metalloproteinase and the cell goes about its migration.

2 conclusions:

1. Insufficient inhibitors and decoy receptors to Metalloproteinases (and others such as Hydroeicosatetraenoic Acid) will have devastating effects.  If genetically the inhibitors are insufficient, and metalloproteinases are expressed massively, and this happens at the endothelial cell, massive and extensive destruction of endothelial cells throughout the body happens, exposing collagen like structures of the blood vessel walls.  This of course trigger extensive activation of platelets and the Thrombosis of TTP-like syndrome.  So in TTP, it is the inhibitor that is lacking.  (ie Von Willebrand cleaving protease inhibitors have also been cited).  And plasmapheresis removes the the Metalloproteinases (and microbial Antigens/toxin when relevent), stopping the onslaught.

2.What is in the Integrin domain is critical, in ADAM-17, the integrin domain is occupied by TNF-alpha, converting enzyme (TACE) which will free and activate the devastating Tumor Necrosis Factor.  Released massively, TNF can not only induce Apoptosis like certain other Cyclins (interleukine and Interferon ), but also leads directly to NECROSIS.  A massive uncontrolled septic-like syndrome kills rats after infusion of TNF.

ADAM 10, the disintegrin there gives you Amyloid structures of Alzheimer's.  TO BE SHORT, PICK THE ADAM AND SEE THE CONSEQUENT DISEASE ON YOUR OWN!

ADAM! A FLIPPASE, FLOPPASE AND/OR A SCRAMBLASE-LIKE MOLECULE !

HYPOTHESIS : WHERE DO CYCLINS COME FROM?

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

(E2F AND CYCLIN E, ARE POWERFUL TARGETS FOR CANCER CURE)

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)
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THE INTEGRINS, PRESUMED SOURCE OF CYCLINS!

Early detection of Lung Cancer

LUNG CANCER EARLY DETECTION:

CRBCM IS SEEKING FUNDING FOR A STUDY TO SEE WHETHER CURRENT MOLECULAR TESTING COULD DETECT EARLY LUNG CANCER IN SELECTED GROUPS OF HEAVY SMOKERS.  WE PLAN TO SELECT 150 HEAVY SMOKERS (HISTORY OF 60 PACK A YEAR).
OBTAIN SEQUENCIAL SERUM LEVELS OF E-CADHERIN, METALLOPROTEINASE, AND TUMOR GROWTH FACTOR BETA (EVERY 3 MONTHS FOR 1 YEAR).  A PET SCAN WILL BE OBTAINED AT DAY 1 AND DAY 365.  SELECTED INDIVIDUALS  WILL BE OBSERVED FOR 3-5 YEARS THERE AFTER WITH YEARLY CHECK OF MARKERS AFTER THE FIRST YEAR.

ALTHOUGH PET FINDINGS ARE CRITICAL FOR OUR EVALUATION, WHAT WE ARE CONCENTRATING ON IS TO SEE WHETHER THESE "TUMOR MARKERS" FOLLOWED SEQUENTIALLY COULD PREDICT LUNG CANCER IN HEAVY SMOKERS.

IT WOULD BE INTERESTING TO SEE THE LEVELS OF THESE MARKERS ON PATIENTS WITH INCIDENTAL POSITIVE PET FINDINGS.  ANOTHER COROLLARY MEASUREMENT WILL SCREEN FOR ANA AND RHEUMATOID FACTOR TO SEE WHETHER COEXISTING AUTOIMMUNE DISEASES AFFECT THE PATTERN OF THESE MARKERS, PARTICULARLY THE TGF.
SHOULD THESE FINDINGS BE SIGNIFICANT, A TRIPLE KIT COULD BE DEVELOPED FOR EARLY DETECTION OF LUNG CANCER.