The p53 gene and cancer development

The p53 Gene and Cancer Development

P53-GENE-Cover

Do Your Genetics Control Your Health?

For years our parents and grandparents were told that there health outcomes were based around the genetic characteristics they inherited from their parents.  While our genetics do play an important role in our physiology, the broad based perspective that medical science perpetuated was that genetic material is the most important factor in our health outcomes.

Today, we understand that many aspects of our genetics are controlled by the environmental factors that we interact with on a daily basis.  This is called epigenetics, or genetic adaptation through environmental stimuli (1).  Epigenetics is a field of genetics, in which variations are caused by environmental stimuli that switch genes on and off and affect how the cells read specific genes (2).

Let’s take a closer look at the difference between genetic and epigenetic expression when it comes to our health.

Genetic Polymorphism:  This is a change in the DNA sequence in a particular genotype.  An example would be Down’s Syndrome which has a triple chromosome at 21.  This third chromosome (we should only have 2) leads to growth abnormalities and mental retardation.  This is a process that happens during the congenital period of development in the mother’s womb

Epigenetic Adaptation:  This is a change in the genetic expression without any sort of modification in the DNA sequence.  Certain genes are switched on and off based around the environmental stimuli that is acting upon them (2).  These adaptations happen after birth as the individual is exposed to various environmental inputs and there genes adapt to these experiences.

p53_HumanGenome

Genetic and Epigenetic Expression

While the particular eye color and skin color you have are based on the DNA sequencing in your cells, the development of chronic disease is a result of epigenetics or how the environment you have been exposed too has altered your genetic expression (3).

This is good news, because if we can alter our genetic expression for the worse by lifestyle and environment, it also means we can improve our genetic expression through positive lifestyle habits. Reducing stress, eating good foods, avoid toxins, going through periodic cleanses, having positive relationships and getting adequate rest all help to protect our genetic stability and reduce the risk of developing chronic disease.

Screen-Shot-2013-04-26-at-11.47.13-AM

The p53 Gene and Cancer Development

One genetic protein that scientists are studying in detail for its role in cancer cell development is the p53 gene.  P53 acts as a guardian of the DNA by acting as a checkpoint in the cell cycle process (4).  When it senses abnormalities in the growth cycle, it activates the p21 gene which binds to the cell division-stimulating protein (cdk2) to stop the cell cycle.

While the normal cell cycle is stopped, the cellular enzymes initiate a DNA repair process.  If the DNA is able to be repaired, the p53 gene will allow the cell to go back into its normal cycle of growth and reproduction.  If the DNA cannot be repaired, than p53 signals for cellular apoptosis (programmed cell death) (5).

In a sense, p53 acts as a security guard to make sure that abnormal cellular growth does not occur.  Its job is to ensure that the proper cellular data is used to ensure the future expression of the organism.  In order to carry out its job, p53 regulates the expression of hundreds of genes and is in the elite hierarchy of proteins in the cell (6).

Think of p53 like the Presidential security team.  If they feel threatened, with one phone call they can instantly shut down a city.  In the same way, p53’s position is to guard and regulate the cellular cycle to maintain the highest level of function required by the body.

Slide1

Oxidative Stress and the p53 Gene

Oxidative stress is an imbalance between the production of free radicals and the body’s ability to counteract or neutralize their harmful effects through anti-oxidants.   In response to low levels of oxidative stresses, p53 exhibits antioxidant activities to eliminate oxidative stress and ensure cell survival; in response to high levels of oxidative stresses, p53 exhibits pro-oxidative activities that further increase the levels of stresses, leading to cell death (7).

The p53 gene will basically get a sense of the environment and the cell’s ability to serve the body well.  If it believes in the value of the cell it will help protect the life of the cell by resisting the free radical damage.

If it doesn’t feel as though the cell is strong enough or healthy enough to serve the needs of the body, it will stimulate more cell damage, leading to cellular death.  These functions of p53 prevent the passage of DNA damage to the daughter cells and thus maintain genomic stability.

nrm4007-f3

Epigenetic Mutations in p53

Research has shown that epigenetic mutations from chronic oxidative stress damage the protein matrix in the p53 gene and are a major factor in the development of cancer.  This mutation leads to an inability for the gene to block abnormal cellular growth (8).

Some forms of the mutation produce a type of p53 protein that actually stimulates cell division and promotes the development of highly invasive cancers that are more apt to metastasize and more commonly fatal (9).

f0209

Toxicity and p53 Gene Activity

Chronic oxidative stress can cause damage to the p53 gene that renders it useless and leads to an inability to protect the genomic stability.   In order to be active, p53 needs to bind zinc while other metals such as copper can displace zinc leading to p53 unfolding. Low zinc levels or excessive copper and other heavy metals such as lead, aluminum, cadmium and mercury can damage the p53 protein (10, 11).

Many other environmental toxins can lead to damaged p53 activity and increased cancer growth.  This includes the following:

Pesticide exposure (12)

Herbicide exposure (13)

Chlorine exposure (14)

Fluoride exposure (15)

Air Pollution (PCAH) exposure (16)

Radiation exposure (17)

Many factors involved with an unhealthy diet and lifestyle increase oxidative stress, mutate the p53 gene and increase the risk of cancer.  This includes the following

High blood sugar (18)

Fried Foods (HCA’s & acrylamide) (19)

Trans Fats & (20)

x122270839735000274

Natural Compounds that Protect p53

Many natural compounds act as potent anti-oxidants and protect the body from high levels of oxidative stress.  These compounds protect the p53 gene function and allow it to remain stable so it can adequately perform its role of protecting the genome from abnormal cell development.

Some of these compounds that can be found in natural food sources include:

Glutathione (21) found in sulfur foods such as onions, garlic, milk thistle & cruciferous veggies among others

Sulforaphane (22) found in cruciferous vegetables and sprouts

Curcumin (23) found in turmeric

Anthocyanins (24) found in berries, red cabbage & red onions among others

Catechins (25) found in green tea, raw cacao, carab, apple skins and pecans

Stilbenes (26) such as resveratrol found in berries and grape skins

Carotenoids (27) found in a number of fruits, vegetables and pasture-raised animal foods

p53CompoundsGraphic

Strengthening Your p53 Genes

The research is clear that the stability of your p53 genes is one of the most important factors in your risk for developing life-threatening cancers.  Although genetically inherited traits play a role in the health of your p53 genes, the most important factors are of an epigenetic nature that includes your exposure to environmental stress, carcinogenic chemicals and poor lifestyle habits.

Avoiding exposure to environmental toxins and consuming foods rich in positive genetic modifyers are critically important.  These are things that for the most part you are in control of!  Every day, you choose the foods you consume and the lifestyle habits you embark upon that you either be contributing to the mutation or the strengthening of your p53 gene activity.

CancerCleanseFreePDF

Sources For This Article Include:

  1. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010 Oct;28(10):1057-68. PMID: 20944598
  2. Weinhold B. Epigenetics: The Science of Change. Environmental Health Perspectives. 2006;114(3):A160-A167.
  3. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27-36.
  4. Lane DP. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15-6. PMID: 1614522
  5. Adimoolam S, Ford JM. p53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair (Amst). 2003 Sep 18;2(9):947-54. PMID: 12967652
  6. Gudkov A. Microarray analysis of p53-mediated transcription: multi-thousand piece puzzle or invitation to collective thinking. Cancer Biol Ther. 2003 Jul-Aug;2(4):444-5. PMID: 14508118
  7. Liu D, Xu Y. p53, Oxidative Stress, and Aging. Antioxidants & Redox Signaling. 2011;15(6):1669-1678.
  8. Marrogi AJ, Khan MA, van Gijssel HE, Welsh JA, Rahim H, Demetris AJ, Kowdley KV, Hussain SP, Nair J, Bartsch H, Okby N, Poirier MC, Ishak KG, Harris CC. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma. J Natl Cancer Inst. 2001 Nov 7;93(21):1652-5. PMID: 11698570
  9. Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013 Jan;15(1):2-8. PMID: 23263379
  10. Metal toxicity and the p53 protein: an intimate relationship Link Here
  11. Tokumoto M, Fujiwara Y, Shimada A, Hasegawa T, Seko Y, Nagase H, Satoh M. Cadmium toxicity is caused by accumulation of p53 through the down-regulation of Ube2d family genes in vitro and in vivo. J Toxicol Sci. 2011 Apr;36(2):191-200. PMID: 21467746
  12. Calaf GM, Echiburu-Chau C, Roy D. Organophosphorous pesticides and estrogen induce transformation of breast cells affecting p53 and c-Ha-ras genes. Int J Oncol. 2009 Nov;35(5):1061-8. PMID: 19787260
  13. Takeyama N, Tanaka T, Yabuki T, Nakatani T. The involvement of p53 in paraquat-induced apoptosis in human lung epithelial-like cells. Int J Toxicol. 2004 Jan-Feb;23(1):33-40. PMID: 15162845
  14. Rought SE, Yau PM, Schnier JB, Chuang LF, Chuang RY. The effect of heptachlor, a chlorinated hydrocarbon insecticide, on p53 tumor suppressor in human lymphocytes. Toxicol Lett. 1998 Jan 16;94(1):29-36. PMID: 9544696
  15. Ha J, Chu Q, Wang A, Xia T, Yang K. [Effects on DNA damage and apoptosis and p53 protein expression induced by fluoride in human embryo hepatocytes]. Wei Sheng Yan Jiu. 2004 Jul;33(4):400-2. Chinese. PMID: 15461257
  16. Mordukhovich I, Rossner P Jr, Terry MB, Santella R, Zhang YJ, Hibshoosh H, Memeo L, Mansukhani M, Long CM, Garbowski G, Agrawal M, Gaudet MM, Steck SE, Sagiv SK, Eng SM, Teitelbaum SL, Neugut AI, Conway-Dorsey K, Gammon MD. Associations between polycyclic aromatic hydrocarbon-related exposures and p53 mutations in breast tumors. Environ Health Perspect. 2010 Apr;118(4):511-8. PMID: 20064791
  17. Fei P, El-Deiry WS. P53 and radiation responses. Oncogene. 2003 Sep 1;22(37):5774-83. PMID: 12947385
  18. Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J. Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes. 2001 Oct;50(10):2363-75. PMID: 11574421
  19. Durling LJ, Abramsson-Zetterberg L. A comparison of genotoxicity between three common heterocyclic amines and acrylamide. Mutat Res. 2005 Feb 7;580(1-2):103-10. PMID: 15668112
  20. Chung FL, Pan J, Choudhury S, Roy R, Hu W, Tang MS. Formation of trans-4-hydroxy-2-nonenal- and other enal-derived cyclic DNA adducts from omega-3 and omega-6 polyunsaturated fatty acids and their roles in DNA repair and human p53 gene mutation. Mutat Res. 2003 Oct 29;531(1-2):25-36. PMID: 14637245
  21. Wang H, Luo K, Tan LZ, Ren BG, Gu LQ, Michalopoulos G, Luo JH, Yu YP. p53-induced gene 3 mediates cell death induced by glutathione peroxidase 3. J Biol Chem. 2012 May 11;287(20):16890-902. PMID: 22461624
  22. Chew YC, Adhikary G, Wilson GM, Xu W, Eckert RL. Sulforaphane induction of p21(Cip1) cyclin-dependent kinase inhibitor expression requires p53 and Sp1 transcription factors and is p53-dependent. J Biol Chem. 2012 May 11;287(20):16168-78. PMID: 22427654
  23. Jee SH, Shen SC, Tseng CR, Chiu HC, Kuo ML. Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells. J Invest Dermatol. 1998 Oct;111(4):656-61. PMID: 9764849
  24. Liu W, Lu X, He G, et al. Protective Roles of Gadd45 and MDM2 in Blueberry Anthocyanins Mediated DNA Repair of Fragmented and Non-Fragmented DNA Damage in UV-Irradiated HepG2 Cells. International Journal of Molecular Sciences. 2013;14(11):21447-21462.
  25. Hastak K, Gupta S, Ahmad N, Agarwal MK, Agarwal ML, Mukhtar H. Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. Oncogene. 2003 Jul 31;22(31):4851-9. PMID: 12894226
  26. Ferraz da Costa DC, Casanova FA, Quarti J, Malheiros MS, Sanches D, Dos Santos PS, Fialho E, Silva JL. Transient transfection of a wild-type p53 gene triggers resveratrol-induced apoptosis in cancer cells. PLoS One. 2012;7(11):e48746. PMID: 23152798
  27. Nishino H, Tokuda H, Murakoshi M, Satomi Y, Masuda M, Onozuka M, Yamaguchi S, Takayasu J, Tsuruta J, Okuda M, Khachik F, Narisawa T, Takasuka N, Yano M. Cancer prevention by natural carotenoids. Biofactors. 2000;13(1-4):89-94. PMID: 11237205

CancerCleanseFreePDF

Print Friendly

Comments

comments

Get Your FREE Guide to the SuperCharged Recipe Plan - Click to Learn More
No comments yet.

Leave a Reply