title: Molecular Mechanism of Regulation of MTA1 Expression by Granulocyte Colony-stimulating Factor.
abstract: Parkinson disease (PD) is a neurodegenerative disorder with loss of dopaminergic neurons of the brain, which results in insufficient synthesis and action of dopamine. Metastasis-associated protein 1 (MTA1) is an upstream modulator of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and hence MTA1 plays a significant role in PD pathogenesis. To impart functional and clinical significance to MTA1, we analyzed MTA1 and TH levels in the substantia nigra region of a large cohort of human brain tissue samples by Western blotting, quantitative PCR, and immunohistochemistry. Our results showed that MTA1 and TH levels were significantly down-regulated in PD samples as compared with normal brain tissue. Correspondingly, immunohistochemistry analysis for MTA1 in substantia nigra sections revealed that 74.1% of the samples had a staining intensity of <6 in the PD samples as compared with controls, 25.9%, with an odds ratio of 8.54. Because of the clinical importance of MTA1 established in PD, we looked at agents to modulate MTA1 expression in neuronal cells, and granulocyte colony-stimulating factor (G-CSF) was chosen, due to its clinically proven neurogenic effects. Treatment of the human neuronal cell line KELLY and acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model with G-CSF showed significant induction of MTA1 and TH with rescue of phenotype in the mouse model. Interestingly, the observed induction of TH was compromised on silencing of MTA1. The underlying molecular mechanism of MTA1 induction by G-CSF was proved to be through induction of c-Fos and its recruitment to the MTA1 promoter.
authors.affiliation: From the Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai 600 036 and.
authors.forename: Arathy S
authors.initials: AS
authors.lastname: Kumar
authors.affiliation: From the Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai 600 036 and.
authors.forename: Sankar
authors.initials: S
authors.lastname: Jagadeeshan
authors.affiliation: From the Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai 600 036 and.
authors.forename: Anirudh
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: the Centre for Toxicology and Developmental Research (CEFT).
authors.forename: Saravana Babu
authors.initials: SB
authors.lastname: Chidambaram
authors.affiliation: Departments of Human Genetics.
authors.forename: Rohan Prasad
authors.initials: RP
authors.lastname: Surabhi
authors.affiliation: From the Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai 600 036 and.
authors.forename: Mahak
authors.initials: M
authors.lastname: Singhal
authors.affiliation: Departments of Human Genetics.
authors.forename: Hemadev
authors.initials: H
authors.lastname: Bhoopalan
authors.affiliation: the Centre for Toxicology and Developmental Research (CEFT).
authors.forename: Sathiya
authors.initials: S
authors.lastname: Sekar
authors.affiliation: Community Medicine, and.
authors.forename: Ravi Shankar
authors.initials: RS
authors.lastname: Pitani
authors.affiliation: Pathology, Sri Ramachandra University, Porur, Chennai 600 116, India.
authors.forename: Prathiba
authors.initials: P
authors.lastname: Duvuru
authors.affiliation: Departments of Human Genetics, ganeshv@sriramachandra.edu.in.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkatraman
authors.affiliation: From the Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai 600 036 and rayala@iitm.ac.in.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Rayala
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000378:metabolism; D015534:Trans-Activators; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D006655:Histone Deacetylases; D004298:Dopamine
keywords: Parkinson disease; dopamine; growth factor; nuclear receptor; transcription coregulator