Katherine Jones (academic)

Last updated
Katherine A. Jones
Kathy-Jones-Headshot.jpg
Alma mater University of California, Riverside
Known for HIV, stem cell biology, proteomics
Scientific career
Institutions Salk Institute for Biological Studies

Katherine A. Jones is a professor of regulatory biology and the Edwin K. Hunter Chair at the Salk Institute for Biological Studies. She uses proteomics to study transcription elongation and molecular biology to understand protein coordination. Jones identified elongation factors, a class of proteins which are important in viral gene expression.

Contents

Early life and education

Jones earned her PhD in biochemistry at the University of California, Riverside. She was made a Pew Scholar in 1987. [1] Her Pew Foundation fellowship allowed her to study the transcription mechanisms that are responsible for rapid induction in mammalian genes. [2] Jones showed how the RNA polymerase II transcription factor Sp1 binds to DNA and activates RNA. [3]

Research and career

Jones is a professor of regulatory biology and Edwin K. Hunter Chair at the Salk Institute for Biological Studies. Jones holds an adjunct position at University of California, San Diego. [4] She has worked extensively on understanding the Human Immunodeficiency Virus (HIV). [5] She investigated several proteins that interact with HIV-Tat (Tat). [6] Tat is a protein created by HIV, which has been described as an "engine for HIV replication". [7] Jones identified several proteins (including Cyclin T1, CycT1, and SSu72) that are required for HIV gene expression. [8] SSu72 is a phosphatase that binds to Tat and speeds up the transcription process that replicates the virus. [6] Unfortunately, CycT1 is needed for normal cell function, so is not an ideal target for antivirals. [6]

Jones looks to create small molecule inhibitors that restrict these proteins. [1] She identified that the small molecule JIB-04 is particularly effective in destroying Tat. She used DIFFpop to identify the protein targets of JIB-04. DIFFpop revealed that JIB-04 decreases the levels of Tat because it binds together two enzymes in the host cell, SHMT2 and BRCC36, which subsequently enable the cells to destroy Tat. [9] At present JIB-04 is too toxic to primary T-cells, but Jones and colleagues are working on investigations of other small molecules that can still inhibit Tat expression. [9]

Jones demonstrated that in colon cancer, the mutated adenomatous polyposis coli (APC) regulates the expression of genes which control cancer growth. [10] She demonstrated that APC cannot turn off growth control genes as it cannot bind to a protein that presents metastasis. [11] She has gone on to show that transcription elongation is involved with the differentiation of stem cells. It is well known that wnt and activin pathways are needed for stem cell growth, but it was unclear how they work together. Jones showed how they work together to activate transcription. She also demonstrated that activation of the wnt signaling pathway can result in colon cancer. [12] During their investigations of embryonic stem cells, Jones identified a third pathway, YAP, which slows the activin pathway and stops stem cells from specialising. [13] She used CRISPR-cas9 to remove the genes that make the YAP protein, reducing the number of steps to convert embryonic stem cells into functional heart cells. [13] [14]

She has also studied the CDK12 gene, which is mutated in 3 - 5% of prostate, ovarian and breast cancers. [15] The majority of cancers that contain a mutated CDK12 gene are not responsive to immunotherapy, so creating inhibitors of CDK12 could make cancers more treatable. [15] When CDK12 is inhibited cells cannot repair DNA and the cells are more likely to die during chemotherapy. [15]

In 2017 Jones filed a lawsuit against the Salk Institute for Biological Studies for gender discrimination, citing that their work had not been recognised their labs were small and they received less funding. [16] [17] She claimed that imagery of women faculty members was used in Salk Institute promotional material to secure funding from donors. [16] Jones settled her case in August 2018. [18] [19]

Related Research Articles

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">CREB-binding protein</span> Nuclear protein that binds to CREB

CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

<span class="mw-page-title-main">P-TEFb</span>

The positive transcription elongation factor, P-TEFb, is a multiprotein complex that plays an essential role in the regulation of transcription by RNA polymerase II in eukaryotes. Immediately following initiation Pol II becomes trapped in promoter proximal paused positions on the majority of human genes. P-TEFb is a cyclin dependent kinase that can phosphorylate the DRB sensitivity inducing factor (DSIF) and negative elongation factor (NELF), as well as the carboxyl terminal domain of the large subunit of Pol II and this causes the transition into productive elongation leading to the synthesis of mRNAs. P-TEFb is regulated in part by a reversible association with the 7SK snRNP. Treatment of cells with the P-TEFb inhibitors DRB or flavopidirol leads to loss of mRNA production and ultimately cell death.

<span class="mw-page-title-main">Cyclin-dependent kinase 9</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.

<span class="mw-page-title-main">Cyclin T1</span> Protein-coding gene in humans

Cyclin-T1 is a protein that in humans is encoded by the CCNT1 gene.

<span class="mw-page-title-main">POLR2E</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerases I, II, and III subunit RPABC1 is a protein that in humans is encoded by the POLR2E gene.

<span class="mw-page-title-main">Cyclin-dependent kinase 7</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the CDK7 gene.

<span class="mw-page-title-main">POLR2L</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerases I, II, and III subunit RPABC5 is a protein that in humans is encoded by the POLR2L gene.

<span class="mw-page-title-main">POLR2K</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerases I, II, and III subunit RPABC4 is a protein that in humans is encoded by the POLR2K gene.

<span class="mw-page-title-main">SUPT5H</span> Protein-coding gene in the species Homo sapiens

Transcription elongation factor SPT5 is a protein that in humans is encoded by the SUPT5H gene.

<span class="mw-page-title-main">GTF2H4</span> Protein-coding gene in the species Homo sapiens

General transcription factor IIH subunit 4 is a protein that in humans is encoded by the GTF2H4 gene.

<span class="mw-page-title-main">HTATSF1</span> Protein-coding gene in the species Homo sapiens

HIV Tat-specific factor 1 is a protein that in humans is encoded by the HTATSF1 gene.

<span class="mw-page-title-main">GTF2F2</span> Protein-coding gene in the species Homo sapiens

General transcription factor IIF subunit 2 is a protein that in humans is encoded by the GTF2F2 gene.

<span class="mw-page-title-main">Cyclin K</span> Protein-coding gene in the species Homo sapiens

Cyclin-K is a protein that in humans is encoded by the CCNK gene.

<span class="mw-page-title-main">DSIF</span>

DSIF is a protein complex that can either negatively or positively affect transcription by RNA polymerase II. It can interact with the negative elongation factor (NELF) to promote the stalling of Pol II at some genes, which is called promoter proximal pausing. The pause occurs soon after initiation, once 20-60 nucleotides have been transcribed. This stalling is relieved by positive transcription elongation factor b (P-TEFb) and Pol II enters productive elongation to resume synthesis till finish. In humans, DSIF is composed of hSPT4 and hSPT5. hSPT5 has a direct role in mRNA capping which occurs while the elongation is paused.

Tat (HIV)

In molecular biology, Tat is a protein that is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101 amino acids depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.

Beverly M. Emerson is an Emeritus Professor of Biological Sciences at the Salk Institute for Biological Studies who uncovered details about how cancer becomes drug resistant. She is currently at the Oregon Health & Science University’s Knight Cancer Institute. She is a Fellow of the American Association for the Advancement of Science.

References

  1. 1 2 "Katherine Jones". Salk Institute for Biological Studies. Retrieved 2019-04-23.
  2. ↑ "Katherine A. Jones, Ph.D." bit.ly. Retrieved 2019-04-23.
  3. ↑ Kadonaga, James T.; Jones, Katherine A.; Tjian, Robert (1986). "Promoter-specific activation of RNA polymerase II transcription by Sp1". Trends in Biochemical Sciences. 11 (1): 20–23. doi:10.1016/0968-0004(86)90226-4. ISSN   0968-0004.
  4. ↑ "Katherine A. Jones". biology.ucsd.edu. Retrieved 2019-04-23.
  5. ↑ Jones, Katherine A.; Peterlin, B. Matija (1994). "Control of Rna Initiation and Elongation at the Hiv-1 Promoter". Annual Review of Biochemistry. 63 (1): 717–743. doi:10.1146/annurev.bi.63.070194.003441. PMID   7979253.
  6. 1 2 3 A new dent in HIV-1's armor , retrieved 2019-04-24
  7. ↑ "Discovery reveals how cells try to control levels of key HIV protein". ScienceDaily. Retrieved 2019-04-24.
  8. ↑ Wei, Ping; Garber, Mitchell E; Fang, Shi-Min; Fischer, Wolfgang H; Jones, Katherine A (February 1998). "A Novel CDK9-Associated C-Type Cyclin Interacts Directly with HIV-1 Tat and Mediates Its High-Affinity, Loop-Specific Binding to TAR RNA". Cell. 92 (4): 451–462. doi: 10.1016/s0092-8674(00)80939-3 . ISSN   0092-8674. PMID   9491887. S2CID   16395032.
  9. 1 2 "Small Molecule Appears to Destroy Protein That Wakes Dormant HIV". MD Magazine. Retrieved 2019-04-24.
  10. ↑ Jones, Katherine. "Mechanism of beta-Catenin and APC-Regulated Transcription at Wnt Target Genes". Grantome.
  11. ↑ Sierra, Jose; Yoshida, Tomonori; Joazeiro, Claudio A.; Jones, Katherine A. (2006-03-01). "The APC tumor suppressor counteracts β-catenin activation and H3K4 methylation at Wnt target genes". Genes & Development. 20 (5): 586–600. doi:10.1101/gad.1385806. ISSN   0890-9369. PMC   1410807 . PMID   16510874.
  12. ↑ Vital step in stem cell growth revealed , retrieved 2019-04-24
  13. 1 2 Getting straight to the heart of the matter in stem cells , retrieved 2019-04-24
  14. ↑ "Salk Institute | The Stem Cellar" . Retrieved 2019-04-24.
  15. 1 2 3 "New role for a driver of metastatic cancers". EurekAlert!. Retrieved 2019-04-24.
  16. 1 2 Wadman, Meredith (2017-07-19). "Salk Institute under fire for 'smear' on women suing it for discrimination". Science | AAAS. Retrieved 2019-04-24.
  17. ↑ Pickett, Mallory (2019-04-18). "I Want What My Male Colleague Has, and That Will Cost a Few Million Dollars". The New York Times. ISSN   0362-4331 . Retrieved 2019-04-24.
  18. ↑ Maxmen, Amy (2018-08-18). "Salk Institute asks judge to narrow scope of gender-discrimination suit". Nature. doi:10.1038/d41586-018-06013-z. S2CID   81798888.
  19. ↑ "Joint Statement from Salk President Dr. Rusty Gage, on behalf of the Salk Institute, and Salk Professors Drs. Kathy Jones and Vicki Lundblad". Salk Institute for Biological Studies. Retrieved 2019-04-24.
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