Tax gene product

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A Tax Gene Product (Tax) is a nuclear protein that has a molecular weight of about 37,000 to 40,000 daltons.

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Tax gene

Tax is produced by members of the retroviral family primate T-lymphotropic virus, which are classified as Deltaretroviruses. This includes Human T-lymphotrophic viruses (HTLVs), bovine leukaemia virus (BLV) and simian T-lymphotropic viruses (STLVs). The tax protein produced from HTLV-1 and HTLV-2 have been most extensively studied. [1] The gene for Tax is found within the pX region between the env gene and one of the long terminal repeats of the viral genome; which is where the name Tax comes from (transactivator from the X-gene region). Tax acts as a transactivator, causing the transcription (production of mRNA from genetic code) of viral proteins in the long terminal repeat that are essential for replication. [2] [3] [4]

Role in disease

HTLV-1 causes an aggressive form of leukaemia: adult T cell leukaemia (ATL), and Tax has largely been implicated in the oncogenic potential of this virus. In addition to Tax's ability to promote the transcription of viral proteins in the nucleus, it also regulates many human genes. It does this by modulating the activity of several signaling pathways such as: CREB/ATF, NF-κB, AP-1 and SRF. [4] Tax modulates cellular processes by protein-protein interaction (binding with proteins), transcriptional activation (promoting the production of proteins) and transcriptional repression (inhibiting the production of proteins). Cellular processes that Tax dysregulates to produce cancerous cells include the cell cycle and the maintenance of genomic integrity. The cell cycle has four stages (G1, S, G2 and M) and Tax is known to accelerate the transition between G1 and S phase. Two DNA repair pathways (base excision repair and nucleotide excision repair) are affected by Tax, leading to mutations in DNA; a classical hallmark of cancer. Tax also causes aneuploidy (abnormal chromosome numbers), which is a possible cause of transformation (normal cells becoming cancer cells). Many proteins are involved in these processes, including cyclins and cell cycle checkpoint proteins (p53 and Rb). [4] Interesting, HTLV-1 Tax viral gene is known to dampen innate antiviral signaling pathways to avoid host detection and elimination, through SOCS1 and Aryl Hydrocarbon Receptor Interacting Protein (AIP). [5] [6]

Although Tax from HTLV-1 and HTLV-2 can cause cells to become cancerous experimentally, Tax produced by HTLV-2 is less oncogenic than that from HTLV-1 and therefore is thought to be the reason that HTLV-2 is not associated with ATL. [1]

Related Research Articles

Interferon Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

Retrovirus Family of viruses

A retrovirus is a type of virus that inserts a copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus.

In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein.

Human T-lymphotropic virus 1 Species of virus

Human T-cell lymphotropic virus type 1' or human T-lymphotropic virus (HTLV-I), also called the adult T-cell lymphoma virus type 1, is a retrovirus of the human T-lymphotropic virus (HTLV) family that has been implicated in several kinds of diseases including very aggressive adult T-cell lymphoma (ATL), HTLV-I-associated myelopathy, uveitis, Strongyloides stercoralis hyper-infection and some other diseases. It is thought that about 1–5% of infected persons develop cancer as a result of the infection with HTLV-I over their lifetimes.

Oncovirus Viruses that can cause cancer

An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their RNA virus origin. With the letters "RNA" removed, it now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus". The vast majority of human and animal viruses do not cause cancer, probably because of longstanding co-evolution between the virus and its host. Oncoviruses have been important not only in epidemiology, but also in investigations of cell cycle control mechanisms such as the retinoblastoma protein.

Viral pathogenesis is the study of the process and mechanisms by which viruses cause diseases in their target hosts, often at the cellular or molecular level. It is a specialized field of study in virology.

Aryl hydrocarbon receptor

The aryl hydrocarbon receptor is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originally thought to function primarily as a sensor of xenobiotic chemicals and also as the regulator of enzymes such as cytochrome P450s that metabolize these chemicals. The most notable of these xenobiotic chemicals are aromatic (aryl) hydrocarbons from which the receptor derives its name.

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Interferon type I

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XBP1

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IRF7

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AH receptor-interacting protein

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IFITM1

Interferon-induced transmembrane protein 1 is a protein that in humans is encoded by the IFITM1 gene. IFITM1 has also recently been designated CD225. This protein has several additional names: fragilis, IFI17 [interferon-induced protein 17], 9-27 [Interferon-inducible protein 9-27] and Leu13.

Rev is a transactivating protein that is essential to the regulation of HIV-1 protein expression. A nuclear localization signal is encoded in the rev gene, which allows the Rev protein to be localized to the nucleus, where it is involved in the export of unspliced and incompletely spliced mRNAs. In the absence of Rev, mRNAs of the HIV-1 late (structural) genes are retained in the nucleus, preventing their translation.

HBx

HBx is a hepatitis B viral protein. It is 154 amino acids long and interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host. It forms a heterodimeric complex with its cellular target protein, and this interaction dysregulates centrosome dynamics and mitotic spindle formation. It interacts with DDB1 redirecting the ubiquitin ligase activity of the CUL4-DDB1 E3 complexes, which are intimately involved in the intracellular regulation of DNA replication and repair, transcription and signal transduction.

Human T-lymphotropic virus Informal grouping of virus species

The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and a demyelinating disease called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLVs belong to a larger group of primate T-lymphotropic viruses (PTLVs). Members of this family that infect humans are called HTLVs, and the ones that infect Old World monkeys are called Simian T-lymphotropic viruses (STLVs). To date, four types of HTLVs and four types of STLVs have been identified. HTLV types HTLV-1 and HTLV-2 viruses are the first retroviruses which were discovered. Both belong to the oncovirus subfamily of retroviruses and can transform human lymphocytes so that they are self-sustaining in vitro. The HTLVs are believed to originate from interspecies transmission of STLVs. The HTLV-1 genome is diploid, composed of two copies of a single-stranded RNA virus whose genome is copied into a double-stranded DNA form that integrates into the host cell genome, at which point the virus is referred to as a provirus. A closely related virus is bovine leukemia virus BLV. The original name for HIV, the virus that causes AIDS, was HTLV-3.

Human T-lymphotropic virus 2 Species of virus

A virus closely related to HTLV-I, human T-lymphotropic virus 2 (HTLV-II) shares approximately 70% genomic homology with HTLV-I. It was discovered by Robert Gallo and colleagues.

Simian-T-lymphotropic viruses, also Simian T-cell leukemia viruses (STLVs), are retroviruses closely related to the human sexually and breastfeeding transmissible viruses HTLV. They have subtypes 1 through 4 as compared to HTLV 1 through 4, and each subtype has its own serovars. Together they comprise PTLVs A study has shown that STLV-1 Tax and SBZ proteins have similar functions to their counterparts of HTLV-1. STLV-1 is oncogenic in Japanese macaques.

An interferon-stimulated gene (ISG) is a gene that can be expressed in response to stimulation by interferon. Interferons bind to receptors on the surface of a cell, initiating protein signaling pathways within the cell. This interaction leads to the expression of a subset of genes involved in the innate immune system response. ISGs are commonly expressed in response to viral infection, but also during bacterial infection and in the presence of parasites.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

References

  1. 1 2 Romanelli, MG; Diani, E; Bergamo, E; Casoli, C; Ciminale, V; Bex, F; Bertazzoni, U (Sep 9, 2013). "Highlights on distinctive structural and functional properties of HTLV Tax proteins". Frontiers in Microbiology. 4: 271. doi:10.3389/fmicb.2013.00271. PMC   3766827 . PMID   24058363.
  2. ↑ Womack, edited by W. Jean Dodds, James E. (1997). Molecular genetics, gene transfer, and therapy. San Diego, Calif.: Academic Press. ISBN   0120392410.CS1 maint: extra text: authors list (link)
  3. ↑ Ross, TM; Pettiford, SM; Green, PL (Aug 1996). "The tax gene of human T-cell leukemia virus type 2 is essential for transformation of human T lymphocytes". Journal of Virology. 70 (8): 5194–202. PMC   190475 . PMID   8764028.
  4. 1 2 3 Jeang, KT; Giam, CZ; Majone, F; Aboud, M (Jul 30, 2004). "Life, death, and tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation". The Journal of Biological Chemistry. 279 (31): 31991–4. doi: 10.1074/jbc.r400009200 . PMID   15090550.
  5. ↑ Charoenthongtrakul, Soratree; Zhou, Qinjie; Shembade, Noula; Harhaj, Nicole S.; Harhaj, Edward W. (2011-07-15). "Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF-κB-Dependent Induction of SOCS1". Journal of Virology. 85 (14): 6955–6962. doi:10.1128/JVI.00007-11. ISSN   0022-538X. PMC   3126571 . PMID   21593151.
  6. ↑ Zhou, Qinjie; Lavorgna, Alfonso; Bowman, Melissa; Hiscott, John; Harhaj, Edward W. (2015-06-05). "Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon". Journal of Biological Chemistry. 290 (23): 14729–14739. doi:10.1074/jbc.M114.633065. ISSN   0021-9258. PMC   4505538 . PMID   25911105.
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