Transcription Factor

In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. (1,2)

The function of TFs is to regulate (turn on and off) genes in order to make sure that they are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism. (See videos below for visual understanding)

Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life; cell migration and organization (body plan) during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone.

There are up to 2600 TFs in the human genome, 1000 of which need zinc (See Zinc finger file).

TFs work alone or with other proteins in a complex, by promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA) to specific genes. (3,4,5)

A defining feature of TFs is that they contain at least one DNA-binding domain (DBD), which attaches to a specific sequence of DNA adjacent to the genes that they regulate. (6,7)

TFs are grouped into classes based on their DBDs. (8,9)

Other proteins such as coactivators, chromatin remodelers, histone acetyltransferases, histone deacetylases, kinases, and methylases are also essential to gene regulation, but lack DNA-binding domains, and therefore are not TFs. (10) Likewise with trace minerals.

TFs are of interest in mainstream allopathic medicine because TF mutations can cause specific diseases, and profit-making medications can be potentially targeted toward them. TFs are also of interest in the holistic medicine field, but holistic researchers prefer to first tweak the endogenous TF system with holistic interventions.

Transcription factors are essential for the regulation of gene expression and are, as a consequence, found in all living organisms. See video below.

Disorders and Cancers

Due to their important roles in development, intercellular signaling, and cell cycle, some human diseases have been associated with mutations in transcription factors. (11)

Many transcription factors are either tumor suppressors or oncogenes, and, thus, mutations or aberrant regulation of them is associated with cancer. Three groups of transcription factors are known to be important in human cancer: the NF-kappaB and AP-1 families,  the STAT family and  the steroid receptors. (12)

Approximately 10% of currently prescribed drugs directly target the nuclear receptor class of transcription factors. Examples include tamoxifen and bicalutamide for the treatment of breast and prostate cancer, respectively, and various types of anti-inflammatory and anabolic steroids. (13).

In addition, transcription factors are often indirectly modulated by drugs through signaling cascades. It might be possible to directly target other less-explored transcription factors such as NF-κB with drugs. (14)

Transcription factors outside the nuclear receptor family are thought to be more difficult to target with small molecule therapeutics since it is not clear that they are “drugable”. This is where holistic and lifestyle interventions may be able to show their strength.

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Discussion & Tentative Conclusion

It is common in biology for important processes to have multiple layers of regulation and control. This is also true with transcription factors: Not only do transcription factors control the rates of transcription to regulate the amounts of gene products (RNA and protein) available to the cell but transcription factors themselves are regulated (often by other transcription factors). Below is a brief synopsis of some of the ways that the activity of transcription factors can be regulated and on how TF are related with regard to carcinogenesis.

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References

  1.  Latchman DS (December 1997). “Transcription factors: an overview”. The International Journal of Biochemistry & Cell Biology. 29 (12): 1305–12. doi:10.1016/S1357-2725(97)00085-X. PMC 2002184. PMID 9570129.
  2. ^ Karin M (February 1990). “Too many transcription factors: positive and negative interactions”. The New Biologist. 2 (2): 126–31. PMID 2128034.
  3. ^ Roeder RG (September 1996). “The role of general initiation factors in transcription by RNA polymerase II”. Trends in Biochemical Sciences. 21 (9): 327–35. doi:10.1016/0968-0004(96)10050-5. PMID 8870495.
  4. ^ Nikolov DB, Burley SK (January 1997). “RNA polymerase II transcription initiation: a structural view”. Proceedings of the National Academy of Sciences of the United States of America. 94 (1): 15–22. Bibcode:1997PNAS…94…15N. doi:10.1073/pnas.94.1.15. PMC 33652. PMID 8990153.
  5. ^ Lee TI, Young RA (2000). “Transcription of eukaryotic protein-coding genes”. Annual Review of Genetics. 34: 77–137. doi:10.1146/annurev.genet.34.1.77. PMID 11092823.
  6. ^ Mitchell PJ, Tjian R (July 1989). “Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins”. Science. 245 (4916): 371–8. Bibcode:1989Sci…245..371M. doi:10.1126/science.2667136. PMID 2667136.
  7. ^ Ptashne M, Gann A (April 1997). “Transcriptional activation by recruitment”. Nature. 386 (6625): 569–77. Bibcode:1997Natur.386..569P. doi:10.1038/386569a0. PMID 9121580.
  8.  Jin J, Zhang H, Kong L, Gao G, Luo J (January 2014). “PlantTFDB 3.0: a portal for the functional and evolutionary study of plant transcription factors”. Nucleic Acids Research. 42 (Database issue): D1182–7. doi:10.1093/nar/gkt1016. PMC 3965000. PMID 24174544.
  9.  Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, Reuter I, Chekmenev D, Krull M, Hornischer K, Voss N, Stegmaier P, Lewicki-Potapov B, Saxel H, Kel AE, Wingender E (January 2006). “TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes”. Nucleic Acids Research. 34 (Database issue): D108–10. doi:10.1093/nar/gkj143. PMC 1347505. PMID 16381825.
  10. Brivanlou AH, Darnell JE (February 2002). “Signal transduction and the control of gene expression”. Science. 295 (5556): 813–8. Bibcode:2002Sci…295..813B. doi:10.1126/science.1066355. PMID 11823631.
  1. ^ Semenza, Gregg L. (1999). Transcription factors and human disease. Oxford [Oxfordshire]: Oxford University Press. ISBN 978-0-19-511239-9.
  2. ^ Libermann TA, Zerbini LF (February 2006). “Targeting transcription factors for cancer gene therapy”. Current Gene Therapy. 6 (1): 17–33. doi:10.2174/156652306775515501. PMID 16475943.
  3. Gronemeyer H, Gustafsson JA, Laudet V (November 2004). “Principles for modulation of the nuclear receptor superfamily”. Nature Reviews. Drug Discovery. 3 (11): 950–64. doi:10.1038/nrd1551. PMID 15520817.
  4.  Bustin SA, McKay IA (June 1994). “Transcription factors: targets for new designer drugs”. British Journal of Biomedical Science. 51 (2): 147–57. PMID 8049612.

Glossary

gene expression– the process by which information from a gene is used in the synthesis of a functional gene product such as a protein

transcription– the process of making messenger RNA(mRNA) from a DNAtemplate by RNA polymerase

transcription factor– a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription

transcriptional regulationcontrollingthe rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA

upregulation, activation, or promotion– increasethe rate of gene transcription

downregulation, repression, or suppression– decreasethe rate of gene transcription

coactivator– a protein that works with transcription factors to increasethe rate of gene transcription

corepressor– a protein that works with transcription factors to decreasethe rate of gene transcription

response element– a specific sequence of DNA that a transcription factor binds to

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