Sunday, June 2, 2013

THE CURE IS WITHIN REACH,
DON'T GET DISTRACTED, FOCUS ON WHAT IS AT STAKE
ONE CLEAR PATH, THE ROLE OF BIM GENE FOR THE CURE!
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Past use of chemotherapy and early interventions have shown us that cancer killing is possible by chemotherapy drug use, by radiation, by infection induced Cytokines, and by the immune system itself.   One of the major pathway to death, is the CELLULAR PROGRAMMED DEATH CALLED APOPTOSIS.
We have now sufficient compelling evidences that all the cancer cell needs to die is to be provided critical circumstances or message that given these conditions pathway to Apoptosis is the logical attitude to adopt!
Aside from chemotherapy and target therapies, severe sepsis delivers the same message to our white cells and other cells, with death of the individual as a result.

Cellular nature provides us with several opportunities to kill the cell, but our knowledge is at present not enough to talk to cell appropriately, and give instructions for Apoptosis.  So for now we try the rough ways!  We kind of brutalize the cell and see what comes out!  And we are still doing so because our knowledge of how the cell work remains rudimentary and fragmented at best.

With our fragmented knowledge, we know now that when we give Etoposide, one of the cell protection mechanism at Mitochondrial level is Bcl-2, and we call this molecule ANTI-APOPTOTIC MOLECULE because it protects the cell against programmed cell death.

But to be fair, nature also gives a chance to cell killing by providing a close Molecule to Bcl-2 called Bcl2L11, which has that BH-3 characteristic, and is PRO-APOPTOTIC, this is the BIM.  Increase this and you have a higher self destruction of cancer cells!  Now how to tell cancer cell, "increase your BIM please!" that where the challenge is!

We have preliminary knowledge, but it needs to be more focused, coordinated and understandable to the cell!
ie. while reviewing MITF gene, we clearly told you that MITF activates RUNX3 and RUNX3 activates BIM, that's the way to do this simply.  But don't kill the messenger, we know this but we really don't know how to every time and effectively achieve this today!

We know a all lot today but not enough ...
 
Here is what we know!
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ATLAS

*BIM is a pro-apoptotic member of the Bcl-2 family important in mediating apoptosis in response to various intrinsic stimuli. Studies using BIM knockout mice showed that it plays a large part in maintaining hematopoietic homeostasis. (THIS GIVE US INSIGHT THAT IN THE BLOOD CELL LINEAGE DISEASE, BIM IS OF A TREMENDOUS IMPORTANCE, AND ACTION AT BIM SHOULD HELP US CONTROL HEMATOLOGIC DISEASES)

*shown to mediate apoptosis in response to stimuli such as cytokine deprivation, deregulated calcium flux and microtubule perturbation. In vivo, BCL2L11/BIM is essential for hematopoietic homeostasis, thymocyte negative selection and as a barrier against autoimmunity. (WHEN STIMULATION OF NERVE CEASES UNDER DEPRIVATION OF NERVE GROWTH FACTOR, BIM GOES TO WORK TO KILL THE NERVE CELL)

*are either bound to DLC1 cytoplasmic dynein light chain and sequestered to the microtubule-associated dynein motor complex or associated with the pro-survival proteins on the mitochondria. A C-terminal hydrophobic domain present in all three major isoforms of BIM localizes the protein to intracytoplasmic membranes. (Making DLC1 a target, IF YOU REMOVE DLC1 FROM THE EQUATION, 2 THINGS MAY HAPPEN, ONE BIM IS FREE TO ACT OR WATCH OUT IT MAY BE MORE DESTROYED BY IBIQUITINATION POTENTIALLY OR "MISLOCATED" MISSING ITS POINT OF ACTION, THESE ARE FACTS WE STILL NEED TO CLEARLY ESTABLISH)

*Gaviraghi et al

  E2F, a characterized transcriptional regulator of BCL2L11 expression. (CHECK OUR BLOG, WE SPOKE ABOUT E2F EXTENSIVELY, HERE IT IS COMING BACK TO REEMPHASIZE ITS "PLAYER STATUS", THIS IS A BOOSTER TO BIM!)
  Expression of BCL2L11 is induced by a diverse range of apoptotic stimuli such as deprivation of growth factors/cytokines, ionizing radiation, and cytotoxic peptides [2,6,14,22].
  Interestingly, the analysis presented in this manuscript indicates that the highest expression levels of BCL2L11 transcripts were detected in pancreas, placenta and thyroid tissue, suggesting an important role for BCL2L11 in the normal physiology of these tissues. With respect to P1-derived transcripts, up to 70% of total BCL2L11 transcripts are contributed from the newly identified promoter in the testis, an organ where BCL2L11 activity was shown to contribute critically to spermatogenesis [25], suggestive for a prominent role for the putative BCL2L11 P1 in the expression of BCL2L11 in this tissue.  (IN WHICH CANCERS AGAIN THIS BIM CAN HAVE A ROLE?)

*atlas!

"BIM-deficient mice developed a fatal systemic lupus erythematosus (SLE)-like disease. Lymphocytes lacking BIM are refractory to a number of stimuli including cytokine deprivation, deregulated calcium ion flux. BIM is also important in turning off immune responses following acute viral infection. BIM cooperates with the death ligand Fas (which triggers the extrinsic pathway) to shut down immune responses following chronic viral infection and to prevent autoimmunity. Experiments using mice deficient for both BIM and pro-survival Bcl-2 demonstrated that Bcl-2 is an essential guardian of BIM. Indeed, removal of just one allele of BIM prevented polycystic kidney disease and restored normal growth of Bcl-2-deficient mice. Loss of both alleles restored a robust hematopoietic system and prevented graying."  (LET'S REEMPHASIZE THAT YOU INDEED HAVE READ THE ROLE OF BIM IN POLYCYSTIC KIDNEY DISEASE, DOES METHYLATING ONE ALLELE A THERAPEUTIC OPTION?)

REGULATION (atlas)

" BIM is regulated by transcriptional control which differs with cell types by transcription factors including FOXO-3a and c-JUN . BIM is also controlled via alternative splicing that produces many different isoforms. BIM is regulated as well by post-translational modifications such as phosphorylation by ERK1, ERK2 and JNK. Phosphorylation-dependant ubiquitylation is thought to regulates BIM's half life.
Interactions:
Unlike some BH3-only proteins, BIM is a promiscuous binder of pro-survival proteins and can bind BCL2, BCLX, BCLW , MCL1 and BCL2A1 with high affinity. There are also some reports that BIMS is able to bind BAX (multidomain pro-apoptotic effector of the pathway) and activate it directly, but whether this binding occurs physiologically is unclear.

BIM belongs to the Bcl-2 family of proteins and contains the BH3 domain which is homologous to the BH3 domains of:"  (EVERY TIME c-JUN IS MENTIONED, I THINK CYTOKINE PRODUCTION, AND CYTOKINES/GROWTH FACTOR DEPENDENT PROCESSES, BLOCKAGE AT RECEPTORS MAY HAVE SIGNIFICANT EFFECTS)





  • The pro-survival proteins: BCL2, BCLX, BCLW, MCL1, BCL2A1/BFL1, Bcl-B/BOO.
  • The multidomain pro-apoptotic proteins: BAX, BAK, BOK.
  • The other BH3-only proteins: PUMA, NOXA, BAD, HRK, BMF, BIK, BID.(NICE TARGETS SIMILAR TO BIM!)  (LET'S GO OUT THERE AND INCREASE THIS STUFF FOR THE CURE!)

  • *1. Hughes et al

      "Bim protein and that NF-Y is important for apoptosis following NGF withdrawal. Furthermore, I found that the transcriptional coactivators CBP/p300 are required for the activation of bim-LUC following NGF withdrawal and that CBP/p300 may interact with NF-Y to enhance bim transcription. In addition to this, the prosurvival MEK/ERK pathway has been found to inhibit bim expression independently of the PI3-K/Akt pathway. 3' RACE and experiments in sympathetic neurons with a new bim-LUC+3'UTR reporter construct revealed that this negative regulation is mediated through the bim 3' UTR. Mutational analysis and RNA stability experiments have been employed to further investigate this mechanism."
    (block NGF all the way, and see what happens!)
    *2. Gilley et al.
      We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation–induced death of sympathetic neurons.
    (WE HAVE SAID, BEHIND THE FOXO LAYS THE PUMA (gene))

    Ong et al.

     Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.
    (RE-EMPHASIZING THE NEED TO HAVE THE RIGHT BIM!)

     IN sepsis Bim is upregulated   Weber et al


    Available online
    http://ccforum.com/content/12/5/R128
    Page 5 of 10
    (page number not for citation purposes)
    ciitis (n = 2), faecal peritonitis (n = 8) and pneumonia (n = 6).
    Nine of the ten critically ill non-septic patients were included in
    their post-operative period afte
    r trauma, abdominal or pharyn-
    geal cancer, or aortic aneurysm rupture with a delayed recov-
    ery. These patients received prophylactic antibiotic treatment
    with no signs of infection in the perioperative phase. One
    patient had abacterial pancreatiti
    s and did not receive antibiot-
    ics. Patients did not receive immunosuppressants or drotrec-
    ogin alfa (activated) before or during their treatment. Eight
    patients with severe sepsis
    received 3 mg/kg hydrocortisone
    before or at the time of sampling. No difference in white blood
    cells counts was found comparing critically ill patients with
    patients with sepsis. However, lymphocyte counts were
    decreased in severe sepsis as compared with critically ill
    patients and dropped below the local reference range of 1–4
    G/l (Table 1).
    Phosphatidylserine externalisation and caspase-3
    activation
    Phosphatidylserine externalisation marks cells for phagocyto-
    sis as an early event of the apoptotic process. Cells were con-
    sidered early apoptotic when phosphatidylserine was
    externalised on cells with a still intact membrane, as indicated
    by negative staining for 7-AAD. CD4
    +
    and CD8
    +
    T-cells and
    CD19
    +
    B-cells exhibited significantl
    y raised portions of phos-
    phatidylserine-positive population
    s in severe sepsis, but not in
    critically ill patients (Figure 1a).
    Caspase-3 is the central executioner caspase. Activation of
    caspase-3 leads to de
    gradation of multiple intracellular sub-
    strates and to the typical morphological features of classical
    apoptosis. In the current study,
    activation of caspase-3 was
    measured by an antibody specific to the active fragment of
    cleaved caspase-3 (Figures 1b and 1c). In patients with
    severe sepsis, the subpopulation
    with active caspase-3 was
    elevated in CD4+ T-cells and CD8+ T-cells compared with
    critically ill patients or healthy
    controls. Also, B-
    cells from sep-
    tic patients were found to cont
    ain significantly more activated
    caspase-3 than B-cells from critically ill patients or healthy
    controls.
    Bcl-2 expression
    Since the Bcl-2 family of proteins is known to regulate the
    mitochondrial integrity, we analysed the expression of Bcl-2
    (Figure 2). The amount of Bcl-2 in CD4
    +
    T-cells of critically ill
    non-septic patients did not differ significantly from healthy con-
    trols. However, in patients with sepsis, Bcl-2 protein levels
    dropped by about 25%. In CD8
    +
    T-cells, no significant change
    between the three groups could be observed. The decrease in
    mitochondrial Bcl-2 was most pronounced in B-cells, where
    Bcl-2 dropped by 36% when compared with healthy controls.
    mRNA expression of Bcl-2 family members
    When investigating the mRNA expression of mobile pro-apop-
    totic BH3-only proteins of the Bcl-2 family, massive induction
    was observed in severe sepsis (Figure 3a). When compared
    with healthy controls and critically ill patients, mRNA expres-
    sion of Bim was upregulated.
    This corresponds to a 310.5-fold
    increase compared with critically ill patients and a 51.7-fold
    rise compared with healthy controls. While Bid was decreased
    in critically ill patients, it was markedly upregulated in severe
    sepsis.
     WE THANK THE RESEARCHER FOR THEIR WORKS WHICH HAVE BROUGHT US CLOSER TO THE CURE, CRBCM RAISES ITS HAT TO YOUR HONOR!   THIS IS REAL SCIENCE DEVOID OF POLITICAL INTRIGUES, JUST PURE PROGRESS, THANK YOU FROM THE BOTTOM OF OUR HEARTS!

    PLENTY OF TARGETS OFFERED HERE!

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