Proteins & Pathways

I have asked the Tox1401 students to use OMIM to do some benzene toxicology annotation. The comments section of this post contains brief descriptions of individual proteins that were identified in two separate benzene screens.

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36 thoughts on “Proteins & Pathways

  1. P21 is a Cyclin-dependent Kinase Inhibitor (CDKN1A). The expression of this gene is strictly controlled by the tumor suppressor gene p53. P21 has been known to inhibit apoptosis; however it does not induce cell death on its own. The p21 gene is found on chromosome 6 in humans. It plays a vital role in the cellular response to DNA damage and an overexpression results in cell cycle arrest. Also, its overexpression in a tumor cell suppresses colony formation, which is similar to that of the cytochrome p53 gene overexpression. P21 is essential for maintaining the G2 phase checkpoint in the human cell cycle.
    In reference to benzene-related toxicity, benzene exposure was found to induce the expression of the p21 gene. As a result, this induces the immediate suppression of the kinetics of hemopoietic progenitors (cells that are present in the blood and bone marrow). The mechanisms of benzene-induced leukemia are due to continuous repetitive changes in hemopoiesis (related to the formation of blood in the body) both during and after benzene exposure. Therefore, the induction of the p21 gene from benzene toxicity causes deleterious changes in blood formation that lead to leukemogenicity.

    Reference: http://omim.org/entry/116899?search=p21&highlight=p21

    • If P21 is essential for maintaining the G2 phase checkpoint in the human cell cycle, why is it bad that benzene exposure induces the expression of P21? Also, P21 inhibits apoptosis, so doesn’t that mean that exposure to benzene would cause P21 to repeat the cell cycle many times?

        • Well, the G2 phase is the last phase in the interphase before mitosis. This phase is characterized by a period of rapid growth in order to prepare for mitosis. So if benzene is inhibiting the expression of p21, we wouldn’t be able to know if cells are growing at the right pace or if they are mutated. With no regulation from the p21 gene, mitosis wouldn’t be properly carried out. In addition, you make a great point about p21 inhibition and apoptosis and technically speaking, the cell cycle would be continuous.

        • I just realized that there was a typo in my original post, i wrote the G2 phase instead of the G1 phase. My apologizes.This phase is the major period of cell growth. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes. This is a crucial phase of the cell cycle.

  2. The CYP2E1 gene encodes an enzyme that is involved in the metabolism of drugs, hormones, and toxins. This gene is located on chromosome 10 and it spans 11,413 basepairs in humans. It also contains 9 exons and a TATA box. CYP2E1 is important for the catalysis of the conversion of ethanol to acetaldehyde and to acetate in humans. The enzyme that CYP2E1 encodes for is important because acetaldehyde is known to play a major role in producing unpleasant symptoms after alcohol intake, such as facial flushing, palpitations, headache, vomiting, and sweating, and in the development of alcohol liver disease. The accumulation of acetaldehyde in liver and blood after drinking alcohol must be determined by the relative rates of its formation and removal, which are influenced by the interactive action of this enzyme in conjunction with the ADH2 and ALDH2 enzymes.
    According to Zhang et al., 2002, CYP2E1 genes are altered after benzene inhalation. In the Hirabayashi et al. paper, the scientists investigated the involvement of the aryl hydrocarbon receptor (AhR) in hematotoxicity using AhR wild-type, heterozygous-KO, and homozygous-KO mice. The mice inhaled benzene at 300ppm for two weeks, but the effects on the CYP2E1 gene are still under investigation. The Zhang et al. paper investigated the effects of benzene metabolism in the liver, but their results were not stated. However, this reader has made the conclusion that since benzene inhalation alters the CYP2E1 gene, which is responsible for the breakdown of toxins in the liver, benzene is not properly broken down and disposed of and can accumulate in the liver, producing harmful effects.

    • When you say that “the reader has made the conclusion” it doesn’t make me fully believe that benzene inhalation alters the CYP2E1 gene. Also, do you know any examples of any harmful effects produced? I’m curious to see what adverse effects occur. Does benzene only accumulate in the liver? What about the kidneys? or even the lungs?:

  3. Mitogen-activated protein kinase 11(MAPK11) also known as P38 is one of the major genes involved in one of the major signaling systems that converts extracellular signals in to cellular responses inside the cell in many eukaryotic cells with the collaboration of some other genes. It is involved in rapid cell division or proliferation, differentiation or when a less specified cell becomes specified like stem cells during maturation, transcription regulation, and development. This protein is located on chromosome 11 and is activated by environmental stresses and by pro inflammatory cytokines, which are regulators of the cell’s response to infections and immune responses that make the infection or disease worse.
    According to the article, “Mechanism of Benzene- Induced Hematotoxicity and Leukemogenicity: Current Review With Implication of Microarray Analyses”, the gene is “…significantly upregulated…” when exposed to benzene meaning that it causes P38 to become more active than it needs to be. The benzene causes pro inflammation inside the cell causing a stress inside resulting in the excess response given by the P38 gene. The gene converts extracellular signals into cellular responses when it is unnecessary, which results in excess proliferation, differentiation of cells, and development along with an excess of transcription regulation forcing the cell to not have enough energy for other processes that do need the energy.

  4. The p130 is part of the retinoblastoma gene. Kong discovered that RBL2 and Rnt1 were essential in controlling telomere length control in human fibroblasts. They concluded that RBL2 interacts with RAD50 and blocks telomere lengthening. The location is on chromosome 16. The removal of 16 chromosomes was associated with diseases such as breast, ovarian, hepatic and prostate cancers. In a rat chromosome the gene is located on chromosome number 19. Fluorescence in situ hybridization is used to detect the gene. The loss of p130 gene resulted in chronic hyperplasia and dysplasia of the small intestinal and colonic epithelium. Hyperplasia occurs when there is an augmentation of cells which can result in benign tumors or cause an organ to enlarge. Dysplasia occurs when there is a proliferation of immature cells and there is a decline in mature cells.
    Haigis proved that retinoblastoma was expressed in all epithelial cells of rats; p107 was expressed in the lower half while p130 was expressed in the upper portion of the chromosome. Differentiated cells in mice expressed p130, while the undifferentiated cells were expressed by p107. The deletion of p130 resulted in high amounts of p107 levels. The benzene upregulates the p130 gene. Upregulation refers to an increase in the number of receptors on surface of target cells. It makes cells highly sensitive to hormones.

    • What exactly does dysplasia do specifically? If this gene makes cells highly sensitive than how does the hormones respond back? Do the hormones than cause more effects because sensitivity is heightened ?? Very interesting gene choice, extremely descriptive and awesome breakdown of what the process does throughout. This helped me to outline my own way of writing for my gene choice, too. Thanks

      • Dysplasia causes abnormal development of organs or cells, it can also cause abnormal structure resulting from such growth.

  5. Gadd 45 is an x-ray responsive gene whose induction is not mediated by protein kinase C, PKC. It can be also called growth arrest- and DNA damage-inducible. Usually, it is a specific gene mainly found in mammalian and other eukaryotic cells. Moreover, it has been discovered that this Gadd45 gene is “highly conversed” and able to convert “a novel 165-amino acid polypeptide” that is almost as the same as the ones in human cells.
    On the other hand, according to Carrier et al. (1994), Gadd45 is primarily a nuclear protein that widely spread in quiescent cells. Some important samples of quiescent cells will be cancer cells and hematopoietic stem cells, which constitute approximately normal bone marrow cells, based on the amount of assay used. Meanwhile, benzene was known to have toxic effects on the hematopoietic system at high level. It shows that even at low levels of benzene exposure can actually lead to a bone marrow toxicity based on a recent experiment that was done in Tianjin, China, where workers exposed to at exposures below 1 ppm. As a result, the amount of hematopoietic stem cells generated in the bone marrow has been reduced by benzene eventually. In the other word, the number of Gadd45 genes would be affected as benzene invades the hematopoietic system.
    Reference: http://omim.org/entry/126335?search=gadd45&highlight=gadd45

    • Informative! If the conversion is almost the same in human cells then it should definitely be able to tell us more about cancer just from the perspective of using x-ray technology which hopefully provides us with some new promising information.

    • hematopoietic stem cells generated in the bone marrow gets reduced by benzene which explains that progenitor cells are more sensitive to the effects of benzene than mature blood cells, that are leading to the observed hematotoxicity.

  6. The p21 gene encodes for cyclin-dependent kinase inhibitor 1A, which is a protein that regulates the cell cycle at the G1 checkpoint. The expression of p21 is upregulated by the p53 gene, and it is usually turned on in response to a stress, such as detected DNA damage. It plays a large role in DNA replication regulation during the S phase of the cell cycle. Therefore, p21 is a tumor suppressor gene. When p21 is expressed, the cell cycle is arrested and the cell usually moves into G0. If CDKN1A interacts with certain caspases, apoptosis of the cell is promoted.
    Exposure to benzene has been shown to effect expression of p21. This causes p21 to code for CDKN1A, which suppresses the cell cycle. This is one major reason for benzene’s hematotoxicity. The effects of benzene are mostly seen in stem/progenitor cells of the bone marrow. When an organism is exposed to benzene, there is shown to be a marked drop in white blood cells, lymphocytes, granulocytes, and several other cells in the bloodstream of that organism. This is because the bone marrow progenitor cells give rise to these cells, so repression of the progenitor cell cell cycle will lead to less production of these differentiated cells. Therefore, hematotoxicity is a major feature of benzene exporsure and the cause at the genetic level is overexpression of p21.

    • Good paper I like how you thoroughly explained the role and effects gene p21 has in the human body. I think you should have linked the p21 gene to benzene exposure closer in you paper to where you began to speak of the effects of benzene exposure however that is just an opinion. Overall it is a very good paper and exemplifies a very important point.

  7. Leukemia is a disease that destroys not just the person infected but everyone close to them. Benzene is an extreme carcinogen that had been linked to a few deadly diseases forms of leukemia included. RAD51 is protein that plays an important role in many of the events happening in a eukaryote cell and has been shown to play a role in benzene toxicity in humans.
    RAD51 has been linked to protection of DNA breaking in HeLa cells which are a form of immortal cells linked to certain cancers. The aid of RAD51 to HeLa cells helps promote cancer because these immortal cells are susceptible to apoptosis. In an experiment using mice with the p53 gene knockout it was found that when exposed to benzene the proteins including RAD51 gained a higher growth.
    According to research conducted by the national institute of health RAD51 is linked aiding benzene intoxication. The RAD51 protein plays a critical role in the protection of benzene intoxication and preservation of the DNA need to cause destruction. Further research can possibly be linked to way to stop such proteins from carrying out their function and thus helping to cure those infected.

  8. PTPalpha

    Protein-tyrosine kinases and protein-tyrosine phosphatases are vital for cellular functions such as cell proliferation and signal transduction. It has especially generated interest because of their suspected involvement in cellular signal transduction. It can be further divided into two classes in which a small, soluble enzyme containing a single conserved PTPase domain. This relates to a T-cell protein-tyrosine phosphatase and can be even larger containing another domain. The amino acid protein has an N-terminal which are the catalytic domains. When mapped the mouse Ptpra gene to chromosome 2, confirming the exceptional homology between human chromosome 20 and the segment of mouse chromosome 2. Furthermore, studies have suggested that PTPalpha might be a useful target in breast and colon cancer therapy, and possible development of isoform-specific therapeutic reagents. Current observations have linked the presence of an intact SH2 domain in Grb2, as well as tyrosine phosphorylation of R-PTP-alpha. Grb2 is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. Grb2 is best known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, ERK1,2. Grb2 is composed of an SH2 domain.This observation links a receptor tyrosine phosphatase with a key component of a central cellular signaling pathway and provides a basis for addressing R-PTP-alpha function.If studies are furthered in this area of research it would open an opportunity to learn in-depth about about cell transduction and proliferation which are essential to understand the complexity behind tumors.

  9. Benzene is a chemical that has been linked to the casuation of cancers in human. It is considered a carcogen due to its effect on the human body. The chemical itself aids in turning off the p53 gene which is a tumor suppressing gene. I know this due to the chart in Yoko Hirabayashi’s article on benzene introduced hematoxicity and leukemogenicity. For non-medicla and scientific personal hematoxicity is when the blood is infected with toxins and usually is comes with acidosis (low blood pH). Benzene causes this because when it is metabolised it causes DNA damage which shuts off the p53 and p21 gene. In turn apoptosis is uncontrolable, meaning cells with problems will not be destroyed or healthy cells will be destroyed accidentally. This disorder is called Aplasitc Anemia, another disease that benzene leads to is leukemia. Which is lack of working/effecitve leukocytes (white blood cells). p53 gene is more closly related to cancers as p21 leads to failure of the apoptosis system. Cells that are effected with benzene can usually kill themselves off with apoptosis so that other cells do not get effected and their DNA is not harmed. But the chemical first turns off the p21 gene which controls this system and then it leads to hematoxcicity and possibly leukemia.

    Reference: Pdf: Yoko Hiryabashi,

  10. CYP2E1 is a gene that encodes an enzyme and it works in the metabolism of hormones, drugs and toxins. This gene has nine exons and a TATA box and it spins at 11,414 bp in human and is located on chromosome 10. P28 is considered the major genes that works in the signaling systems and converts the extracellular signals into cellular responses inside the cell of many eukaryotic cells with the help of other genes. CYP2E1 is important for the catalysis of the conversion of ethanol to acetaldehyde and to acetate in humans. Acetaldehyde is known to play a major role in the production of unwanted symptoms after taking alcohol. They cause facial flushing, headache, vomiting and sweating and causes alcohol liver disease. This is caused by the interactive action of enzyme in conjunction with the ADH2 and ALDH2 enzymes. The article explains that when benzene inhalation alters the CYP2E1 gene it become responsible for the breakdown of toxins in the liver.

    The article also explains that when gene is exposed to benzene it causes P38 to become more active than needed; it causes inflammation inside of the cell. Proliferation and differential of cells also occurs because gene converts extracellular signals into cell responses when it is not needed. It causes for the cell to lose energy and be not able to perform other function, which are needed from the cell.

    • This was a very informative response! I liked the way you explained everything, from the structure of the gene to the function.
      Is P28 and P38 the same as CYP2E1? or is it a typo?
      Also you forgot to post the OMIM site that you used.

  11. RAD51 is a protein that plays a role in the recombination events of eukaryotic cells and the gene that codes for this protein is located on chromosome 6. RAD51 is also a DNA-damage/repair-related gene. RAD51 was founded to be required to protect HeLa cells from agents that cause DNA double-stranded breaks. It was also founded that RAD51 had a selective affinity for branched DNA structures and it stimulated D loop formation, which is an essential step in recombination. With these findings, it was concluded that RAD51 is a pivotal protein to preserve the genome. According to the article “Mechanism of Benzene—Induced Hematotoxicity and Leukemogeniticty: Current Review with Implication of Microarray Analyses,” benzene toxicity causes RAD51 to be upregulated, which means the DNA of the cell wont be copied or fixed properly due to the irregular levels of RAD51. The RAD51 protein plays a critical role in the protection of the DNA needed to destroy the benzene toxicity and the protection of benzene intoxication.

  12. AKT1 is one of three oncogenes homologous that are found in the 3rd Node of the Insulin channel of signals, a protein Kinase-Beta. Phenotypic traits are for the colorectal, ovarian, and breast cancers, as well as the Proteus Syndrome. Location is on Chromosome 14 and a main target of PI3K’s which proliferate cells, survival, differentiation, and the origin stems from the AKT8 murine retrovirus transforming. This specific AKT8 was extracted from the AKR mouse thymoma cell line.
    In referring to the benzene-toxicity of this oncogene; the effects are inflammation and tumor growth by an increasing fold. The AKT1 is immediately again another target first, acting as in a defense line before any further infection can occur within the cells. Mainly the thin line between the spread and the AKT1 defense is the macrophages that help to destroy the toxins.

  13. AKT1 is an oncogene and has a phenotype that reads breast, ovarian, and colorectal cancers and Proteus disease, too. This gene is a protein kinase B-alpha. Located in the channel of insulin primarily, this is only one of three homologous genes. Discovered by cloning methods, in 1987 was cloned and made a 20-fold amplification in one of 5 adrenal cancer tests. Extracted from the isolation of the AKT8 murine retrovirus which is from the mouse thymoma cell line. AKT1 is taken to be from the phospho-loving family of genes and shares in the phosphorylations processed of p27 cells which are promoting cell life, survival, differentiation, and growth. The relation to benzene is that from the first line of defense in the immune system, the AKT1 serves to be present. It binds to the G coupled protein recpetor. Upon benzene toxin exposure, there is massive inflammation and tumor growths due to the interruption of phosphorylation processes. From there the macrophage cells would need to step in as -in vitro – to start the anti-inflammatory process. In cells with activated AKT, wildtype p27 failed to cause G1 arrest, while the anti- effect of mutant p27 cells was not disrupted.

  14. PF4 is a gene that is a potential biomarker of benzene exposure early on because it along with three other genes that were confirmer by qPCR. PF4 codes for Platelet Factor-4 which is a 70 amino acid long protein whose function is to neutralize of herapin-like molecules on the surface of blood vessels. Eisman cloned the PF4 cDNA gene at 1990 sequencing it. The gene itself is a subtype of gene known as the small inducible gene. The gene was also seen in the spleens of NOA mouses that were being examined for their allergic tendencies. It was found in 69% of a protein.PC4 is part of a gene family identified by CXC chemokine family. Chemokines are small basic molecules that regulate traffic of leukocytes. The all have a part in maintaining standard cell state and work in the immune system which explains why it wouldn’t be a far shot to say PF4 may be related to predicting benzene exposure.
    http://omim.org/entry/605398

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