THIS IS A COMPILATION OF EXCERPTS OF RELEVANT SCIENTIFIC WORK SUPPORTING THE FACTS COVERING THE FIRST LAW
NONE OF THE WORK DETAILED HERE COME FROM CRBCM
THIS BLOG IS NOT A SCIENTIFIC SOURCE BUT HELP READER UNDERSTAND THE FUNDAMENTAL BASIS OF THE FIRST LAW "CELL INTEND TO PROTECT INTEGRITY OF DNA AND CELL DIVISION PROCESS". WHEN THAT PROTECTION CAN NOT BE ASSURED, CELL DEATH SHOULD ENSUE. ONE OF THE FIRST THING THAT CANCEROUS CELLS DO IS TO FIGHT THIS LAW AND ALLOW MISTAKE TO BE TOLERATED, HERE ARE THE GENES INVOLVED IN THE FIRST LAW! WE THANK ALL RESEARCHERS CITED BELOW FOR THEIR CONTRIBUTION TO SCIENTIFIC ADVANCE!
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1.NOXA
Noxa (Latin for damage) is a pro-apoptotic member of the Bcl-2 protein family.[4] Bcl-2 family members can form hetero- or homodimers, and they act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The expression of Noxa is regulated by the tumor suppressor p53, and Noxa has been shown to be involved in p53-mediated apoptosis.
Sun et al
Noxa is a BH3-containing mitochondrial protein that contributes to apoptosis by disrupting mitochondrial outer membrane integrity.
Proteasome inhibitor PS-341, the representative of a new class of chemotherapeutic drugs, was capable of inducing apoptosis in cisplatin-resistant SCC cells via the endoplasmic reticulum stress. PS-341 stimulated the phosphorylation of PERK and the unfolded protein response, resulting in the induction of the transcription factor ATF-4. Importantly, the Bcl-2 homology domain 3-only (BH3-only) protein Noxa was found to be strongly induced in cisplatin-resistant SCC cells by PS-341 but not by cisplatin. The knock-down of Noxa using small interference RNA significantly abolished PS-341-mediated apoptosis in SCC cells. Using eIF2α mutant mouse embryonic fibroblasts, we found that functional eIF2α played an essential role in PS-341-induced Noxa expression. Taken together, our novel findings reveal a direct link between PS-341-induced endoplasmic reticulum stress and the mitochondria-dependent apoptotic pathway and suggest that PS-341 may be utilized for overcoming cisplatin-resistance in human SCC.
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2.PUMA:
The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family.[
Fribley et al
Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as Bcl-xL, Bcl-2, Mcl-1, Bcl-w, and A1, inhibiting their interaction with the proapoptotic molecules, Bax and Bak. When the inhibition of these is lifted, they result in the translocation of Bax and activation of mitochondrial dysfunction resulting in release of mitochondrial apoptogenic proteins cytochrome c, SMAC, and apoptosis-inducing factor (AIF) leading to caspase activation and cell death.[1]
Because PUMA has high affinity for binding to Bcl-2 family members, another hypothesis is that PUMA directly activates Bax and/or Bak and through Bax multimerization triggers mitochondrial translocation and with it induces apoptosis.[6][7] Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis.[8][9]
PUMA function is affected or absent in cancer cells
it does not appear that genetic inactivation of PUMA is a direct target of cancer.[3 (wikipedia) Resveratrol acts to inhibit and decrease expression of antiapoptotic Bcl-2 family members while also increasing p53 expression. The combination of these two mechanisms leads to apoptosis via activation of PUMA, Noxa and other proapoptotic proteins, resulting in mitochondrial dysfunction.[48]
3.BAK
willis at al
"Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins"
BAX
The p53 tumor suppressor gene product can induce apoptotic cell death through an unknown mechanism..deficiency in p53 exhibit increases in Bcl-2 and decreases in Bax protein levels in several tissues this can be determined by immunohistochemical and immunoblot methods. (Miyashita et al)
Disruption of the DNA mismatch repair system, characterized by microsatellite instability (MI), plays an important role in the course of human carcinogenesis by increasing the rate of mutations of genes associated with cancers.
mutations of BAX play an important role in the course of carcinogenesis in the stomach, colorectum, and endometrium.Ouyang et al,
Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. Gil-Gomez G, Berns A, Brady HJ.
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Up-regulation of p21WAF1 and Bax and down-regulation of Bcl-2 may be the molecular mechanism through which auristatin-PE inhibits cell growth and induces apoptosis. Li Y, Singh B, AliN,SarkarFH.
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pBax expression may be beneficial in predicting the effects of ACT on patients with IDC. Nio Y, Iguchi C, Yamasawa K, Sasaki S, Takamura M, Toga T, Dong M, Itakura M, Tamura K.Inactivation of the TGFR Beta11 appears to precede BAX Mutation which not only to block Apoptosisbut also to provide selective advantage for growth. (remember at this point the exasperated tumor growth factor is amplified through the stress NF-kB/c-FOS route, and act in a autocrine faction on other susceptible receptor (Lonov et al)
4.BID
This gene encodes a death agonist that heterodimerizes with either agonist BAX or antagonist BCL2. The encoded protein is a member of the BCL-2 family of cell death regulators. It is a mediator of mitochondrial damage induced by caspase-8 (CASP8); CASP8 cleaves this encoded protein, and the COOH-terminal part translocates to mitochondria where it triggers cytochrome c release. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]
Lee et al!
BID, a pro-apoptotic member of the Bcl-2 family, interconnects the extrinsic apoptosis pathway initiated by death receptors to the intrinsic apoptosis pathway.
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5.APAF-1
This gene encodes a cytoplasmic protein that forms one of the central hubs in the apoptosis regulatory network. This protein contains (from the N terminal) a caspase recruitment domain (CARD), an ATPase domain (NB-ARC), few short helical domains and then several copies of the WD40 repeat domain. Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves caspase 9 preproprotein, releasing its mature, activated form. The precise mechanism for this reaction is still debated though work published by Guy Salvesen suggests that the apoptosome may induce caspase 9 dimerization and subsequent autocatalysis.[5] Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.
Alternative splicing results in several transcript variants encoding different isoforms.[2]wikipedia
APAF1 has been shown to interact with NLRP1,[7] Caspase-9,[7][8][9][10][11] APIP,[8] BCL2-like 1[10][11] and HSPA4.[12]
Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis
BCL-2
BCL-2 like
BCLX
MCL-1
CASPASE 3 AND 7
CASPASE 9
P53
c-MYC
