N-myc regulates parkin expression.
Mutations in the parkin gene are common in early-onset and familial Parkinson's disease (PD), and the parkin protein interacts in the ubiquitin-proteasome system as an E3 ligase. However, the regulatory pathways that govern parkin expression are unknown. In this study, we showed that a phylogenetically conserved N-myc binding site in the bi-directional parkin promoter interacted with myc-family transcription factors in reporter assays, and N-myc bound to the parkin promoter in chromatin immunoprecipitation assays and repressed transcription activity. Parkin expression was inversely correlated with N-myc levels in the developing mouse and human brain, in human neuroblastoma cell lines with various levels of n-myc amplification, and in an inducible N-myc cell line. Although parkin and N-myc expression were dramatically altered upon retinoic acid-induced differentiation of a human neuroblastoma cell line, modulation of parkin expression did not significantly affect either rates of cellular proliferation or levels of cyclin E. Analysis of additional genes associated with familial PD revealed a shared basis of transcription regulation mediated by N-myc and the cell cycle. Our results, in combination with functional knowledge of the proteins encoded by these genes, suggest a common pathway linking together PD, the ubiquitin-proteasome system, and cell cycle control.
West
Andrew B
AB
Morris K Udall Center for Parkinson's Disease Research, UCLA Neuropsychiatric Institute, Los Angeles, California 90024, USA. abwest7@yahoo.com
Kapatos
Gregory
G
O'Farrell
Casey
C
Gonzalez-de-Chavez
Fanny
F
Chiu
Kelvin
K
Farrer
Matthew J
MJ
Maidment
Nigel T
NT
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000378:metabolism; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D010300:Parkinson Disease / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
D019927:Cyclin E; D016271:Proto-Oncogene Proteins c-myc; D014212:Tretinoin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein