Ullah Laboratory

Ullah Laboratory - Department of Biology

Research Detailed

Heterotrimeric G-protein mediated cellular signal transduction pathway is the dominant mode of transducing extracellular signal inside the cell. Although the presence of G-protein coupled signal transduction is well documented in diverse biological systems, evidence for a comparable system in plants has just started to accumulate. By utilizing G-protein knock-out alleles in Arabidopsis, our previous works have unraveled diverse G-protein dependent signaling pathways, ranging from auxin, brassinosteroid, gibberellin, ABA, and water-stress. At present, my lab is interested in elucidating the cellular signal transduction pathways mediated by Receptor for Activated Kinase C (RACK1)- a structural homolog of G-protein beta subunit. Major function of RACK1 is perceived to be the integration of signals from different pathways by acting as a scaffold protein. The repertoire of non-plant RACK1 interacting proteins that contain diverse partners ranging from kinases, phosphatases, heterotrimeric G-proteins, ion channels, ribosomes, and membrane and nuclear receptors, established the protein as a multipurpose protein. Though three distinct RACK1 genes, as opposed to a single gene in non-plant organisms, are present in Arabidopsis, essentially nothing is known about their cellular functions. A combination of molecular genetic and cell biological approaches are being utilized to unravel the plant RACK1-mediated signaling pathways. Preliminary results from gene knock-out characterizations implicate RACK1 in plant signaling pathways that are not present in other organisms. Therefore, plant RACK1 studies provide unique opportunities to unravel novel roles for the protein. 

As a part of Plant Biotechnology based project, our lab, with a collaboration from Dr. Sivanesan Dakshanamurthy of Georgetown University, has developed several functional modulators of a plant protein that negatively regulates the environmental stress resistance pathways in crop plants. The same scaffold protein is widely implicated in the translation process of selected viruses. At present, we are evaluating the role of the scaffold protein in the proliferation of the selected viruses. Understanding the precise cellular signaling pathways will allow developing drugs to address diverse viral diseases. 

Hemayet Ullah, is an Associate Professor of Biology at the Howard University, Washington, DC. His lab's main interest is elucidating the scaffold protein mediated cellular signal transduction pathways. His recent works spanned from model plant Arabidopsis response to environmental stress signaling pathways to developing small inhibitor molecules of scaffold protein to use as a broad anti-viral and in the cancer cell metastasis processes. The scaffold protein is implicated in diverse signaling pathways in plants and in human diseases including cancer. The research has resulted in 6 different patent applications spanning for application of these inhibitor 'drugs' for drought/salt stress resistance in crops, for use as a broad anti-viral drug and for use in the inhibition of cancer cell metastasis.

 

ULLAH LABORATOY IN BRIEF

Lab Members

Laboratory Personnel: (Graduate students)

Denver Baptiste - Graduated Summer 2019
Mercy Sabila - Graduated Summer 2018 
Ahasan Rahman - Graduate Student
Albandari Albehishi- Graduated Spring 2016
Shifaa ALshammari - Graduate student
Israa Malli- Graduated Spring 2018
Ghadeer Abdullah- Graduate student

Patents

1.Methods for improving plant agronomical traits by altering the expression or activity of plant G-protein alpha and beta subunits

Publication number: 20040187176

Abstract: The invention provides methods for improving plant agronomic traits by altering the expression or activity of plant G-protein alpha and beta subunits that are GPA1 or AGB1 orthologs. The invention also provides such transgenic plants with improved agronomic traits. One embodiment of the invention includes methods for modulating the expression or activity of a plant G-protein beta subunit that is an AGB1 ortholog to alter one or more of the following: the time to reach and duration of flowering, fruit yield, root biomass, seed size, seed shape, plant size, and the number of stem branches. The present invention also encompasses methods for modulating the expression or activity of a plant G-protein alpha subunit that is a GPA1 ortholog to alter one or more of the following: the duration of flowering, fruit and seed yield, plant size, seed size, and seed shape.

Type: Application
Filed: June 24, 2003
Publication date: September 23, 2004
Inventors: Douglas Boyes, Keith Davis, Alan Jones, Hemayet Ullah, Jin-Gui Chen, Rao Mulpuri, Ani Chatterjee, Mary P. Ward

2. METHODS FOR MODULATING PLANT RESPONSE TO ENVIRONMENTALLY-INDUCED STRESS

Publication number: 20150119250

Abstract: Compounds and methods are described herein that are effective to modulate plant response (e.g., plant susceptibility) to environmentally-induced stress. The compounds and methods described herein advantageously may be used to modulate environmental stress resistance in a wide variety of plants. Environmental stresses include, for example, high light intensity (UV exposure), temperature (e.g., high heat), high soil salinity, and low soil moisture (e.g., drought). As used herein, environmental stresses include any conditions that result in increased generation of reactive oxygen species (ROS) and accumulation of ROS in the plant cells. The compounds described herein that are effective to modulate resistance to the stress prevent, directly or indirectly, or increase phosphorylation of Tyr248 of the RACK1A protein.

Type: Application
Filed: March 15, 2013
Publication date: April 30, 2015
Inventors: Sivanesan Dakshanamurthy, Hemayet Ullah

3. METHODS FOR MODULATING PLANT RESPONSE TO ENVIRONMENTALLY-INDUCED STRESS

Publication number: 20180360043
Abstract: Compounds and methods are described herein that are effective to modulate plant response (e.g., plant susceptibility) to environmentally-induced stress. The compounds and methods described herein advantageously may be used to modulate environmental stress resistance in a wide variety of plants. Environmental stresses include, for example, high light intensity (UV exposure), temperature (e.g., high heat), high soil salinity, and low soil moisture (e.g., drought). As used herein, environmental stresses include any conditions that result in increased generation of reactive oxygen species (ROS) and accumulation of ROS in the plant cells. The compounds described herein that are effective to modulate resistance to the stress prevent, directly or indirectly, or increase phosphorylation of Tyr248 of the RACK1A protein.

Type: Application
Filed: September 5, 2018
Publication date: December 20, 2018
Inventors: Sivanesan Dakshanamurthy, Hemayet Ullah

4. Methods for treating viral infection

Application PCT/US2017/024321
Abstract: A method effective in treating a viral infection involves administering a therapeutically effective amount of at least one compound capable of inhibiting expression of at least a portion of a virus genome containing an internal ribosomal entry site, or a pharmaceutically acceptable salt thereof. The compound has an azole moiety comprising a five member heterocyclic ring containing at least one nitrogen atom, a hydrophobic moiety bonded to the heterocyclic ring of the azole, and a donor / acceptor moiety bonded to the heterocyclic ring having at least one of hydrogen bond donor and a hydrogen bond acceptor.

Inventors: Hemayet Ullah, Sivanesan Dakshanamurthy
2017-03-27
Application filed by Hemayet Ullah, Sivanesan Dakshanamurthy
2017-09-28

Publication of WO2017165885A1

5. U.S. provisional application 62/823,278 filed March 25, 2019.
Our ref: 8823/144534-provisional Title: Drug inhibitor against migration and invasion of cancer
cells and methods of treating against metastasis of cancer cells.

6. U.S. provisional patent application "combination treatment against herpes viruses (e.g.,
method involves administering compounds [e.g., SD-29, SD-11 to SD- 16, SD-111
(renumbered)] with an anti-viral drug (such as acyclovir) or a pro-drug." (Supplement to our
existing patent application on anti-viral drug development (April 26, 2019)

7.  METHOD FOR TREATING AGAINST AN ENTEROVIRUS Application Number 62/752,018, filed October 29, 2018

Publications

Wen F, Armstrong N, Hou W, Cruz-Cosme R, Obwolo LA, Ishizuka K, Ullah H, Luo MH, Sawa A, Tang Q. Zika virus increases mind bomb 1 levels, causing degradation of pericentriolar material 1 (PCM1) and dispersion of PCM1 granules from the centrosome. J Biol Chem. 2019 Oct 30. pii: jbc.RA119.010973. doi: 10.1074/jbc.RA119.010973.

Hemayet Ullah, Wangheng Hou, Sivanesan Dakshanamurthy and Qiyi Tang (2019) Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation Oncotarget, 10:3209-3226.https://doi.org/10.18632/oncotarget.26907

JB Denver, H Ullah (2019) miR393s regulate salt stress response pathway in Arabidopsis thaliana through scaffold protein RACK1A mediated ABA signaling pathways, Plant signaling & behavior Vol 14 (6). https://doi.org/10.1080/15592324.2019.1600394

Mustafa Qasim, Denver Jn Baptiste, and Hemayet Ullah (2017) Optogenetics: A Cellular Photoactivation Method and Its Applications in Biomedical Sciences. International Journal of Bioinformatics and Biomedical Engineering Vol. 3, No. 4, 2017, pp. 27-35https://pdfs.semanticscholar.org/6f99/1800c60ad4559152b17be528208022220ae8.pdf

Ogunwuyi, O., Upadhyay, A., Adesina, S.K., Puri, R., Foreman, T.M., Hauser, B.R., Cox, J., Afoakwah, E., Porter, A., Annan, E., Manka, C., Olatilewa D., Thompson, B., Kibanyi, P.K., Miller, K., and Ullah, H. (2016) Genomic Imprinting: Comparative Analysis Between Plants and Mammals. Plant Tissue Cult. & Biotech. 26(2): 267-284 (December)  https://www.banglajol.info/index.php/PTCB/article/view/30576

Villanueva MA, Islas-Flores T and Ullah H (2016). Signaling through WD-repeat proteins in plants. Front. Plant Sci. 7:1157.doi: 10.3389/fpls.2016.01157

 Sabila M, Kundu N, Smalls D and Ullah H (2016). Tyrosine Phosphorylation Based Homo-dimerization of Arabidopsis RACK1A Proteins Regulates Oxidative Stress Signaling Pathways in yeast.. Front. Plant Sci. 7:176. doi: 10.3389/fpls.2016.00176

Flores, T. I., Rahman, A., Ullah, H., Villanueva, M. A. (2015) The Receptor for Activated C Kinase in Plant Signaling: Tale of a Promiscuous Little Molecule. Frontiers in Plant Science 6.

Elizondo, D; Fernando, L. M; Oliver, E; Clinton, K; Retland, N; Paturault, H; and Ullah, H (2015) Welcome to the Brave New World: CRISPR mediated Genome Editing- pathway to designer babies? Plant Tissue Cult. & Biotech. 25(1): 143-154

Kundu N., Dozier U., Deslandes L., Somssich IE, Ullah, H (2013) Arabidopsis scaffold protein RACK1A interacts with diverse environmental stress and photosynthesis related proteins. Plant Signal Behav. May 2013 Vol 8 (5)

Fennell, H., Olawin, A., Mizanur, R., Ken, I., Chen, JG., Ullah, H. (2012) Arabidopsis scaffold protein RACK1A modulates rare sugar D-allose regulated gibberellin signaling. Plant Signal Behav. 2012 Sep 5;7(11).

Ullah, H., Scappini, E., Moon, AF., Williams, LV., Armstrong, DL., and Pedersen, LC (2009) Crystal Structure of a signal transduction regulator, RACK1 from Arabidopsis thaliana. Protein Sci.17(10):1771-80.

Magee, K., Michael, A., Ullah H., and Dutta, SK. (2007) Dechlorination of PCB in the presence of plant nitrate reductase. Environmental Toxicology and Pharmacology25:144-147

Chen JG, Ullah H, Temple B, Liang J, Guo J, Alonso JM, Ecker JR, Jones AM. (2006) RACK1 mediates multiple hormone responsiveness and developmental processes in Arabidopsis. J Exp Bot, 57: 2697-2708.

Nina M. Storey, NM., Gentile, S., Ullah, H.,Russo, A., Muessel, M., Erxleben, C., and Armstrong, DL. (2006) Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone. Proceedings of the National Academy of Sciences, USA. 103: 5197-5201.

Jones AM, Ullah H, and Chen JG (2003) Dual Pathways for Auxin Regulate Cell Division and Expansion. ed. Nagata, T. Biotechnology in Agriculture and Forestry (Series), .Springer Press. Vol. 53, 181-191.(Book Chapter)

Ullah H, Chen JG, Temple B, Alonso J, Ecker J, Boyes D, Davis K, and Jones AM (2003) Auxin Signaling Coupled by Heterotrimeric G protein in Arabidopsis Lateral Root Formation. Plant Cell 15, 393-409.

Ullah H, Chen JG, and Jones AM (2002) Role of GPA1 in Regulation of Arabidopsis Seed Germination. Plant Physiology 129, 897-907.

Chen JG, Ullah H, Young JC, Sussman MR, Jones AM (2001) ABP1 is Required for Organized Cell Elongation and Division in Arabidopsis Embryogenesis. Genes & Development 15, 902-911 (on cover page)

Ullah H., Chen JG, Young JC, Im KH, Sussman MR, and Jones AM (2001) Modulation of Cell Proliferation by G-protein Alpha Subunit in Arabidopsis. Science 292, 2066-2069.

Ullah H, Clark G, and Islam AS (2001) Internet Resources for Molecular Biology: A Primer for Scientists from Least Developed Countries. Plant Tissue Cult. 11, 195-208, 2001.

Wang XQ, Ullah H, Jones AM, and Assmann S (2001) G protein Regulation of Ion Channels and Abscisic Acid Signaling in Arabidopsis Guard Cells. Science 292, 2070-2072

Lab Highlights

Press release from the University on the anti-viral drug development publication on the coverpage of the journal Oncotarget

http://www.thehabarinetwork.com/howard-university-researchers-release-manuscript-onbreakthrough- for-anti-viral-drugs

The publication link

http://www.oncotarget.com/index.php?journal=oncotarget&page=issue&op=view&path%5B%5D=404

ABSTRACT

Due to the small number of molecular targets in viruses and the rapid evolution of viral genes, it is very challenging to develop specific antiviral drugs. Viruses require host factors to translate their transcripts, and targeting the host factor(s) offers a unique opportunity to develop broad antiviral drugs. It is well documented that some viruses utilize a host protein, Receptor for Activated C Kinase 1 (RACK1), to translate their mRNAs using a viral mRNA secondary structure known as the Internal Ribosomal Entry Site (IRES). RACK1 is essential for the translation of many viruses including hepatitis C (HCV), polio, Drosophila C (DCV), Dengue, Cricket Paralysis (CrpV), and vaccinia viruses. In addition, HIV-1 and Herpes Simplex virus (HSV-1) are known to use IRES as well. Therefore, host RACK1 protein is an attractive target for developing broad antiviral drugs. Depletion of the host’s RACK1 will potentially inhibit virus replication. This background study has led us to the development of novel antiviral therapeutics, such as RACK1 inhibitors. By utilizing the crystal structure of the RACK1A protein from the model plant Arabidopsis and using a structure based drug design method, dozens of small compounds were identified that could potentially bind to the experimentally determined functional site of the RACK1A protein. The SPR assays showed that the small compounds bound strongly to recombinant RACK1A protein. Here we provide evidence that the drugs show high efficacy in inhibition of HSV-1 proliferation in a HEp-2 cell line. The drug showed similar efficacy as the available anti-herpes drug acyclovir and showed supralinear effect when applied in a combinatorial manner. As an increasing number of viruses are reported to use host RACK1 proteins, and more than 100 diverse animals and plant disease-causing viruses are known to use IRES-based translation, these drugs can be established as host-targeted broad antiviral drugs.

Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation

Efficacy of SD29-14 compared with anti-herpes drug acyclovir. (A) Hep-2 cells were incubated with the indicated compounds in the presence of HSV1-Luc virus at a concentration of 4 × 106 pfu/ml media.

Host targeted antiviral (HTA): functional inhibitor compounds of scaffold prote…