Matthias Gromeier

Overview:

Neuro-Oncology
Protein Synthesis Regulation
Signal Transduction
Growth & Proliferation Control in Cancer
Oncolytic Viruses
Viral Neuropathogenesis
Immunization Vectors

Positions:

Professor of Neurosurgery

Neurosurgery, Neuro-Oncology
School of Medicine

Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Professor in Medicine

Medicine, Infectious Diseases
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1992

University of Hamburg (Germany)

Postdoctoral fellow, Molecular Genetics & Microbiology

State University of New York at Stony Brook

Postdoctoral Associate, Molecular Genetics & Microbiology

State University of New York at Stony Brook

Grants:

Recombinant Attenuated Poliovirus Immunization Vectors Targeting H3.3(K27M) in DIPG

Administered By
Neurosurgery, Neuro-Oncology Clinical Research
Role
Co Investigator
Start Date
End Date

Phase-1 clinical trial of PVSRIPO oncolytic immunotherapy in pediatric HGG

Administered By
Neurosurgery
Role
PD/PI
Start Date
End Date

Oncolytic PVSRIPO Expressing Tumor Antigens as a Cancer Vaccine

Administered By
Neurosurgery
Role
Principal Investigator
Start Date
End Date

Oncolytic Poliovirus Immunotherapy of Malignant Glioma

Administered By
Pathology
Role
Co Investigator
Start Date
End Date

Oncolytic Virotherapy of Meningeal Cancer

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Ribosomal RACK1:Protein Kinase C βII Phosphorylates Eukaryotic Initiation Factor 4G1 at S1093 To Modulate Cap-Dependent and -Independent Translation Initiation.

Eukaryotic ribosomes contain the high-affinity protein kinase C βII (PKCβII) scaffold, receptor for activated C kinase (RACK1), but its role in protein synthesis control remains unclear. We found that RACK1:PKCβII phosphorylates eukaryotic initiation factor 4G1 (eIF4G1) at S1093 and eIF3a at S1364. We showed that reversible eIF4G(S1093) phosphorylation is involved in a global protein synthesis surge upon PKC-Raf-extracellular signal-regulated kinase 1/2 (ERK1/2) activation and in induction of phorbol ester-responsive transcripts, such as cyclooxygenase 2 (Cox-2) and cyclin-dependent kinase inhibitor (p21Cip1), or in 5' 7-methylguanosine (m7G) cap-independent enterovirus translation. Comparison of mRNA and protein levels revealed that eIF4G1 or RACK1 depletion blocked phorbol ester-induced Cox-2 or p21Cip1 expression mostly at the translational level, whereas PKCβ inhibition reduced them both at the translational and transcript levels. Our findings reveal a physiological role for ribosomal RACK1 in providing the molecular scaffold for PKCβII and its role in coordinating the translational response to PKC-Raf-ERK1/2 activation.
Authors
Dobrikov, MI; Dobrikova, EY; Gromeier, M
MLA Citation
Dobrikov, Mikhail I., et al. “Ribosomal RACK1:Protein Kinase C βII Phosphorylates Eukaryotic Initiation Factor 4G1 at S1093 To Modulate Cap-Dependent and -Independent Translation Initiation..” Mol Cell Biol, vol. 38, no. 19, Oct. 2018. Pubmed, doi:10.1128/MCB.00304-18.
URI
https://scholars.duke.edu/individual/pub1335035
PMID
30012863
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
38
Published Date
DOI
10.1128/MCB.00304-18

Mitotic phosphorylation of eukaryotic initiation factor 4G1 (eIF4G1) at Ser1232 by Cdk1:cyclin B inhibits eIF4A helicase complex binding with RNA.

During mitosis, global translation is suppressed, while synthesis of proteins with vital mitotic roles must go on. Prior evidence suggests that the mitotic translation shift involves control of initiation. Yet, no signals specifically targeting translation initiation factors during mitosis have been identified. We used phosphoproteomics to investigate the central translation initiation scaffold and "ribosome adaptor," eukaryotic initiation factor 4G1 (eIF4G1) in interphase or nocodazole-arrested mitotic cells. This approach and kinase inhibition assays, in vitro phosphorylation with recombinant kinase, and kinase depletion-reconstitution experiments revealed that Ser1232 in eIF4G1 is phosphorylated by cyclin-dependent kinase 1 (Cdk1):cyclin B during mitosis. Ser1232 is located in an unstructured region of the C-terminal portion of eIF4G1 that coordinates assembly of the eIF4G/-4A/-4B helicase complex and binding of the mitogen-activated protein kinase (MAPK) signal-integrating kinase, Mnk. Intense phosphorylation of Ser1232 in mitosis strongly enhanced the interactions of eIF4A with HEAT domain 2 of eIF4G and decreased association of eIF4G/-4A with RNA. Our findings implicate phosphorylation of eIF4G1(Ser1232) by Cdk1:cyclin B and its inhibitory effects on eIF4A helicase activity in the mitotic translation initiation shift.
Authors
Dobrikov, MI; Shveygert, M; Brown, MC; Gromeier, M
MLA Citation
Dobrikov, Mikhail I., et al. “Mitotic phosphorylation of eukaryotic initiation factor 4G1 (eIF4G1) at Ser1232 by Cdk1:cyclin B inhibits eIF4A helicase complex binding with RNA..” Mol Cell Biol, vol. 34, no. 3, Feb. 2014, pp. 439–51. Pubmed, doi:10.1128/MCB.01046-13.
URI
https://scholars.duke.edu/individual/pub1000416
PMID
24248602
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
34
Published Date
Start Page
439
End Page
451
DOI
10.1128/MCB.01046-13

Evaluation of IRES-mediated, cell-type-specific cytotoxicity of poliovirus using a colorimetric cell proliferation assay.

PVS-RIPO is a recombinant oncolytic poliovirus designed for clinical application to target CD155 expressing malignant gliomas and other malignant diseases. PVS-RIPO does not replicate in healthy neurons and is therefore non-pathogenic in rodent and non-human primate models of poliomyelitis. A tetrazolium salt dye-based cellular assay was developed and qualified to define the cytotoxicity of virus preparations on susceptible cells and to explore the target cell specificity of PVS-RIPO. In this assay, PVS-RIPO inhibited proliferation of U87-MG astrocytoma cells in a dose-dependent manner. However, HEK293 cells were much less susceptible to cell killing by PVS-RIPO. In contrast, the Sabin type 1 live attenuated poliovirus vaccine strain (PV(1)S) was cytotoxic to both HEK293 and U87-MG cells. The correlation between expression of CD155 and cytotoxicity was also explored using six different cell lines. There was little or no expression of CD155 and PVS-RIPO-induced cytotoxicity in Jurkat and Daudi cells. HEK293 was the only cell line tested that showed CD155 expression and resistance to PVS-RIPO cytotoxicity. The results indicate that differential cytotoxicity measured by the colorimetric assay can be used to evaluate the cytotoxicity and cell-type specificity of recombinant strains of poliovirus and to demonstrate lot to lot consistency during the manufacture of viruses intended for clinical use.
Authors
Yang, X; Chen, E; Jiang, H; Muszynski, K; Harris, RD; Giardina, SL; Gromeier, M; Mitra, G; Soman, G
MLA Citation
Yang, Xiaoyi, et al. “Evaluation of IRES-mediated, cell-type-specific cytotoxicity of poliovirus using a colorimetric cell proliferation assay..” J Virol Methods, vol. 155, no. 1, Jan. 2009, pp. 44–54. Pubmed, doi:10.1016/j.jviromet.2008.09.020.
URI
https://scholars.duke.edu/individual/pub721623
PMID
18951922
Source
pubmed
Published In
Journal of Virological Methods
Volume
155
Published Date
Start Page
44
End Page
54
DOI
10.1016/j.jviromet.2008.09.020

The hepatitis C virus 3'-untranslated region or a poly(A) tract promote efficient translation subsequent to the initiation phase.

Enhancement of eukaryotic messenger RNA (mRNA) translation initiation by the 3' poly(A) tail is mediated through interaction of poly(A)-binding protein with eukaryotic initiation factor (eIF) 4G, bridging the 5' terminal cap structure. In contrast to cellular mRNA, translation of the uncapped, non-polyadenylated hepatitis C virus (HCV) genome occurs independently of eIF4G and a role for 3'-untranslated sequences in modifying HCV gene expression is controversial. Utilizing cell-based and in vitro translation assays, we show that the HCV 3'-untranslated region (UTR) or a 3' poly(A) tract of sufficient length interchangeably stimulate translation dependent upon the HCV internal ribosomal entry site (IRES). However, in contrast to cap-dependent translation, the rate of initiation at the HCV IRES was unaffected by 3'-untranslated sequences. Analysis of post-initiation events revealed that the 3' poly(A) tract and HCV 3'-UTR improve translation efficiency by enabling termination and possibly ribosome recycling for successive rounds of translation.
Authors
Bradrick, SS; Walters, RW; Gromeier, M
MLA Citation
Bradrick, Shelton S., et al. “The hepatitis C virus 3'-untranslated region or a poly(A) tract promote efficient translation subsequent to the initiation phase..” Nucleic Acids Res, vol. 34, no. 4, 2006, pp. 1293–303. Pubmed, doi:10.1093/nar/gkl019.
URI
https://scholars.duke.edu/individual/pub721606
PMID
16510853
Source
pubmed
Published In
Nucleic Acids Res
Volume
34
Published Date
Start Page
1293
End Page
1303
DOI
10.1093/nar/gkl019

Expression of the human poliovirus receptor/CD155 gene is activated by sonic hedgehog.

The human poliovirus receptor/CD155 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. The ectodomain of CD155 mediates cell attachment to the extracellular matrix molecule vitronectin, while its intracellular domain interacts with the dynein light chain Tctex-1. CD155 is a primate-restricted gene that is expressed during development in mesenchymal tissues and ventrally derived structures within the CNS. Its function in adults is as yet unknown, but significantly, CD155 is aberrantly expressed in neuroectodermal tumors. We show that the expression of CD155 mRNA is up-regulated when human Ntera2 cells are treated with purified Sonic hedgehog (Shh) protein. Reporter gene expression driven by the CD155 core promoter is activated by Shh in transient co-transfection assays. Analysis of the CD155 core promoter indicates that an intact GLI binding site is required for Shh activation. In addition, overexpression of Gli1 or Gli3 potently activates reporter gene expression driven by the CD155 core promoter. These data identify the CD155 gene as a transcriptional target of Shh, a finding that has significance for the normal function of CD155 during development and the expression of CD155 in neuroectodermal tumors.
Authors
Solecki, DJ; Gromeier, M; Mueller, S; Bernhardt, G; Wimmer, E
MLA Citation
Solecki, David J., et al. “Expression of the human poliovirus receptor/CD155 gene is activated by sonic hedgehog..” J Biol Chem, vol. 277, no. 28, July 2002, pp. 25697–702. Pubmed, doi:10.1074/jbc.M201378200.
URI
https://scholars.duke.edu/individual/pub721618
PMID
11983699
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
277
Published Date
Start Page
25697
End Page
25702
DOI
10.1074/jbc.M201378200