Kevin Struhl

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Kevin Struhl (born September 2, 1952) is an American biochemist and academic who works at Harvard Medical School as the David Wesley Gaiser Professor of Biological Chemistry and Molecular Pharmacology.

Struhl currently studies transcriptional regulatory mechanisms in yeast via a combination of different evolutionary, genetic, molecular, and genomic approaches. He also utilizes these approaches to explain the transcriptional regulatory circuits that control the formation of cancer stem cells and the process of cellular transformation.[1]

Early life and education[]

Struhl was born September 2, 1952 in New York City, New York to Joseph and Harriet Struhl. He attended Great Neck South High School in Long Island from 1966-1970. He enrolled in the Massachusetts Institute of Technology in 1970 where he graduated with a Bachelor of Science and Master of Science in Molecular Biology in 1974. He was then accepted into a Ph.D. program at Stanford University in the department of biochemistry where he earned his Ph.D. with distinction in 1979. Struhl then did a brief postdoctoral study at MRC Laboratory of Molecular Biology in Cambridge, UK from 1980-1982.

Research[]

Work at Stanford[]

In 1976, while at Stanford, Struhl attempted to express functional genes of eukaryotic DNA in the bacterium Escherichia coli. To do this, Struhl cloned specific segments of Saccharomyces cerevisiae (Baker’s yeast) in a bacteriophage and subsequently select for a hybrid phage.[2] The following year, while still at Stanford, Struhl was able to successfully express the eukaryotic gene (his3) that encodes the enzyme imidazoleglycerolphosphate (IGP) dehydratase in yeast and transcribe and translate it into Escherichia coli.[3] This made Struhl the first person to ever express a eukaryotic protein-coding gene (his3) in E. coli.[4] Struhl’s work at Stanford led to a career researching transcriptional regulatory mechanisms that has spanned the past four decades.

Work at MRC[]

In 1986, Struhl was at MRC, where he researched eukaryotic promotor sequences and deletion mapping. His findings supported the conclusion that eukaryotic promoter regions for the his3 gene in S. cerevisiae are large when compared to prokaryotic promoters. Struhl used a heteroduplex-nuclease S1 protection technique and was able to successfully map the 5’ end of the his3 mRNA.[5] Mutants of a ƛhis3 phage were isolated where spontaneous deletions occurred. If mutants were able to retain the structural his3 gene, but had deletion sequences before the 5’ end, they were tested for their in vivo phenotype in yeast cells. His3 mRNA was not made in deletions that retained less than 45 bp upstream from the transcribed region of the gene.[5] Interestingly, Struhl found phenotypical similarity in mutants where deletions that were around 300 bp upstream from the coding region of the mRNA to the wild type gene.[5] Because the Pribnow Box is less than 45 bp from the place of mRNA transcription in E. coli, this suggests that eukaryotic promoters are much larger than prokaryotic promoters.

Work at Harvard[]

In 1992, Struhl showed that TBP was required by all three of the RNA polymerases in yeast cells for transcription alongside Brendan P. Cormack. Struhl inactivated the yeast TBP in vivo via proteolytic and temperature-sensitive derivatives.[6]  In the case of RNA polymerase III, which is required for the synthesis of transfer RNA molecules in eukaryotes and small nuclear RNAs, Struhl found that all three of the genes they examined that are transcribed by this polymerase in yeast were dependent on TBP. The pair utilized an oligonucleotide probe that was complementary to the mature 25S rRNA and the 3’nontranscribed spacer of the precursor RNA.[6] There was a significant decrease in rRNA levels when the cultures were shifted to non-permissive temperatures (37 °C), suggesting TBP is required for transcription by RNA polymerase I.[6] The His3 promoter in yeast contains two proximal sequences, tc and tr that initiate transcription from +1 and +13 elements, respectively. Struhl found that when the cultures were heat inactivated after a shift to 37 °C, there was again a rapid decrease in transcription levels. Because tr elements behaves like TATA elements, but tc exhibits little resemblance to TATA elements, Struhl was able to show that a single TBP in a cell plays a large role in levels of transcription, and moreover that TBP behaves differently at TATA-less promoters.[6]

In 2005, Struhl researched the importance of low nucleosome density and histone-DNA interactions for accessibility of promoter regions in yeast cells. Intrinsic nucleosome stability is necessary for preferential accessibility of transcription factors to bind to promoter regions like the His3-PET56 promoter in yeast.[7] Struhl was able to show this by demonstrating that this promoter region binds poorly to histones in vitro. Utilizing a nucleosome-scanning assay, Struhl demonstrated that accessible region of the promoter was lacking nucleosomes.[7] Through the use of the silencing protein Sir3, Struhl showed that the formation of heterochromatin and its transition from euchromatin occurred over multiple cell cycles.[8] Even when intracellular levels of Sir3 remain constant, transcriptional repression occurs steadily increases for some 3-5 cell generations.[8] An accumulation of this silencing protein is observed in strains lacking the histone acetylase Sas2, which indicates that there are inhibitory effects on heterochromatin formation by these histone modifications.[8]

Recently, Struhl has been focusing on cellular transformation in human cells and how transcriptional regulatory circuits influence molecular pathways and epigenetic switches from non-transformed cells to transformed cells.[9] In a 2009 study, Struhl showed that an inflammatory response that is triggered by an Src oncoprotein and mediated by NF-kB protein complex results in a positive feedback loop that continues an epigenetic transformed state of cells when there is an absence of an inducing signal.[10] The same year, Struhl published a study on the drug Metformin, and its ability to work in combination with a chemotherapeutic agent to act as an anti-cancer therapy to block tumor cell growth. In the study, Struhl and others combined Metformin, which is a drug used to treat type 2 diabetes, with doxorubicin to target cancerous stem cells in mice.[11] They observed that the therapy was able to reduce tumor cell mass and prevent relapse of the cancer, while selectively killing both cancerous stem and non-stem cells in mice.[11]

Awards[]

References[]

  1. ^ "Harvard BBS PhD Program". www.hms.harvard.edu. Retrieved 2021-04-19.
  2. ^ Struhl, Kevin; Davis, Ronald W. (1976), "Genetic Selections and the Cloning of Prokaryotic and Eukaryotic Genes", Molecular Mechanisms in the Control of Gene Expression, Elsevier, pp. 495–506, doi:10.1016/b978-0-12-518550-9.50055-x, ISBN 978-0-12-518550-9, retrieved 2021-04-19
  3. ^ Struhl, K.; Davis, R. W. (1977-12-01). "Production of a functional eukaryotic enzyme in Escherichia coli: cloning and expression of the yeast structural gene for imidazole-glycerolphosphate dehydratase (his3)". Proceedings of the National Academy of Sciences. 74 (12): 5255–5259. Bibcode:1977PNAS...74.5255S. doi:10.1073/pnas.74.12.5255. ISSN 0027-8424. PMC 431671. PMID 341150.
  4. ^ Struhl, Kevin (January 2008). "Kevin Struhl". Current Biology. 18 (1): R7–R9. doi:10.1016/j.cub.2007.10.060. S2CID 18637109.
  5. ^ a b c Struhl, K. (July 1981). "Deletion mapping a eukaryotic promoter". Proceedings of the National Academy of Sciences of the United States of America. 78 (7): 4461–4465. Bibcode:1981PNAS...78.4461S. doi:10.1073/pnas.78.7.4461. ISSN 0027-8424. PMC 319811. PMID 7027262.
  6. ^ a b c d Cormack, Brendan P.; Struhl, Kevin (May 1992). "The TATA-binding protein is required for transcription by all three nuclear RNA polymerases in yeast cells". Cell. 69 (4): 685–696. doi:10.1016/0092-8674(92)90232-2. PMID 1586947. S2CID 7419671.
  7. ^ a b Sekinger, Edward A.; Moqtaderi, Zarmik; Struhl, Kevin (June 2005). "Intrinsic Histone-DNA Interactions and Low Nucleosome Density Are Important for Preferential Accessibility of Promoter Regions in Yeast". Molecular Cell. 18 (6): 735–748. doi:10.1016/j.molcel.2005.05.003. PMID 15949447.
  8. ^ a b c Katan-Khaykovich, Yael; Struhl, Kevin (2005-06-15). "Heterochromatin formation involves changes in histone modifications over multiple cell generations". The EMBO Journal. 24 (12): 2138–2149. doi:10.1038/sj.emboj.7600692. ISSN 0261-4189. PMC 1150886. PMID 15920479.
  9. ^ "Kevin Struhl". bcmp.hms.harvard.edu. Retrieved 2021-04-19.
  10. ^ Iliopoulos, Dimitrios; Hirsch, Heather A.; Struhl, Kevin (November 2009). "An Epigenetic Switch Involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 Links Inflammation to Cell Transformation". Cell. 139 (4): 693–706. doi:10.1016/j.cell.2009.10.014. PMC 2783826. PMID 19878981.
  11. ^ a b "Correction: Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission". Cancer Research. 69 (22): 8832–8833. 2009-11-15. doi:10.1158/0008-5472.CAN-09-3869. ISSN 0008-5472.
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