Whole foods, clean environment, less toxins can strengthen p53 gene – anti-cancer

Epigenetic factors are clearly responsible for increasing your risk of developing fatal cancers. While the genetics you inherited from your parents do play a role in health, the influence from epigenetic factors is one of the greatest factors which can both help or harm your p53 genes. Strengthen your p53 gene activity by reducing your exposure to toxins and choosing healthy lifestyle habits.

Consuming a diet rich in antioxidants will help your p53 genes function optimally and prevent abnormal cells from both growing and dividing. Each day you have a choice to choose habits which will feed cancer or prevent it. Which do you choose?

Whole foods:

  • Vegetables, fruits, and pasture-raised animal food sources are abundant in carotenoids
  • Sprouts and cruciferous vegetables are excellent sources of sulforaphane
  • Turmeric is high in curcumin
  • Pecans, apple skins, green tea, and raw cacao contain a natural compound known as catechins
  • Milk thistle, cruciferous vegetables, onions, and garlic are great sources of the potent antioxidant glutathione
  • Berries, red onions, and red cabbage contain a compound known as anthocyanins
  • Grape skins and berries contain sources of stilbenes including resveratrol

p53 , resveratrol , pancreatic cancer and apoptosis

Intrigued by pancreatic cancer, infection and environmental toxins, I stumble into this topic from Wiki. One of my clients died of stomach , esophagal and pancreatic cancer. Previous to that , he had shingles and other infections.  Her immune system became weaker during the last 5 years before his death.  He disregarded stomach pains and takes TUMs regularly and other anti-viral med for his shingles. His autopsy revealed stomach cancer.


The p53 mechanism functions as a critical signaling pathway in cell growth, which regulates apoptosis, cell cycle arrest, metabolism and other processes 10. In pancreatic cancer, most cells have mutations in p53 protein, causing the loss of apoptotic activity.

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.[3][4] In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene.[3][4]

The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.[5]


The PUMA protein is part of the BH3-only subgroup of Bcl-2 family proteins. This group of proteins only share sequence similarity in the BH3 domain, which is required for interactions with Bcl-2-like proteins, such as Bcl-2and Bcl-xL.[3] Structural analysis has shown that PUMA directly binds to antiapoptotic Bcl-2 family proteins via an amphiphatic α-helical structure which is formed by the BH3 domain.[6] The mitochondrial localization of PUMA is dictated by a hydrophobic domain on its C-terminal portion.[7] No posttranslational modification of PUMA has been discovered yet.[5]

Mechanism of action

Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as Bcl-xLBcl-2Mcl-1Bcl-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 dysfunctionresulting in release of mitochondrial apoptogenic proteins cytochrome cSMAC, and apoptosis-inducing factor(AIF) leading to caspase activation and cell death.[3]

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.[8][9] Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis.[10][11]



The majority of PUMA induced apoptosis occurs through activation of the tumor suppressor protein p53. p53 is activated by survival signals such as glucose deprivation[12] and increases expression levels of PUMA. This increase in PUMA levels induces apoptosis through mitochondrial dysfunction. p53, and with it PUMA, is activated due to DNA damage caused by a variety of genotoxic agents. Other agents that induce p53 dependent apoptosis are neurotoxins,[13][14] proteasome inhibitors,[15] microtubule poisons,[16] and transcription inhibitors.[17] PUMA apoptosis may also be induced independently of p53 activation by other stimuli, such as oncogenic stress[18][19] growth factor and/or cytokine withdrawal and kinase inhibition,[4][20][21] ER stress, altered redox status,[22][23] ischemia,[8][24] immunemodulation,[25][26] and infection.[5][27]


PUMA levels are downregulated through the activation of caspase-3 and a protease inhibited by the serpase inhibitor N-tosyl-L-phenylalanine chloromethyl ketone, in response to signals such as the cytokine TGFβ, the death effector TRAIL or chemical drugs such as anisomycin.[28] PUMA protein is degraded in a proteasome dependent manner and its degradation is regulated by phosphorylation at a conserved serine residue at position 10.[29]

Role in cancer

Several studies have shown that PUMA function is affected or absent in cancer cells. Additionally, many human tumors contain p53 mutations,[30] which results in no induction of PUMA, even after DNA damage induced through irradiation or chemotherapy drugs.[31] Other cancers, which exhibit overexpression of antiapotptic Bcl-2family proteins, counteract and overpower PUMA-induced apoptosis.[32] Even though PUMA function is compromised in most cancer cells, it does not appear that genetic inactivation of PUMA is a direct target of cancer.[33][34][35] Many cancers do exhibit p53 gene mutations, making gene therapies that target this gene [clarification needed] impossible, but an alternate pathway may be to focus on therapeutic to target PUMA and induce apoptosis in cancer cells. Animal studies have shown that PUMA does play a role in tumor suppression, but lack of PUMA activity alone does not translate to spontaneous formation of malignancies.[36][37][38][39][40]Inhibiting PUMA induced apoptosis may be an interesting target for reducing the side effects of cancer treatments, such as chemotherapy, which induce apoptosis in rapidly dividing healthy cells in addition to rapidly dividing cancer cells.[5]

PUMA can also function as an indicator of p53 mutations. Many cancers exhibit mutations in the p53 gene, but this mutation can only be detected through extensive DNA sequencing. Studies have shown that cells with p53 mutations have significantly lower levels of PUMA, making it a good candidate for a protein marker of p53 mutations, providing a simpler method for testing for p53 mutations.[41]

Cancer therapeutics

Therapeutic agents targeting PUMA for cancer patients are emerging. PUMA inducers target cancer or tumor cells, while PUMA inhibitors can be targeted to normal, healthy cells to help alleviate the undesired side effects of chemo and radiation therapy.[5]

Cancer treatments

Research has shown that increased PUMA expression with or without chemotherapy or irradiation is highly toxic to cancer cells, specifically lung,[42] head and neck,[43]esophagus,[44] melanoma,[45] malignant glioma,[46] gastric glands,[47] breast[48] and prostate.[49] In addition, studies have shown that PUMA adenovirus seems to induce apoptosis more so than p53 adenovirus.[42][43][44] This is beneficial in combating cancers that inhibit p53 activation and therefore indirectly decrease PUMA expression levels.[5]

Resveratrol, a plant-derived stilbenoid, is currently under investigation as a cancer treatment. Resveratrol acts to inhibit and decrease expression of antiapoptotic Bcl-2family 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

Tumor protein p53 activated by DNA damage- UV and oxidative stress

Tumor protein p53, also known as p53, cellular tumor antigen p53(UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice).

This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor.[4]

As such, p53 has been described as “the guardian of the genome” because of its role in conserving stability by preventing genome mutation.[5] Hence TP53 is classified as a tumor suppressor gene.[6][7][8][9][10] (Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.)

p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,[41] osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.

The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF.

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible.

The novel molecule MI-63 binds to MDM2 making the action of p53 again possible in situations were p53’s function has become inhibited.[42]

A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress