The p75NTR-interacting protein SC1 inhibits cell cycle progression by transcriptional repression of cyclin E.
Schwann cell factor 1 (SC1), a p75 neurotrophin receptor-interacting protein, is a member of the positive regulatory/suppressor of variegation, enhancer of zeste, trithorax (PR/SET) domain-containing zinc finger protein family, and it has been shown to be regulated by serum and neurotrophins. SC1 shows a differential cytoplasmic and nuclear distribution, and its presence in the nucleus correlates strongly with the absence of bromodeoxyuridine (BrdU) in these nuclei. Here, we investigated potential transcriptional activities of SC1 and analyzed the function of its various domains. We show that SC1 acts as a transcriptional repressor when it is tethered to Gal4 DNA-binding domain. The repressive activity requires a trichostatin A-sensitive histone deacetylase (HDAC) activity, and SC1 is found in a complex with HDACs 1, 2, and 3. Transcriptional repression exerted by SC1 requires the presence of its zinc finger domains and the PR domain. Additionally, these two domains are involved in the efficient block of BrdU incorporation by SC1. The zinc finger domains are also necessary to direct SC1's nuclear localization. Lastly, SC1 represses the promoter of a promitotic gene, cyclin E, suggesting a mechanism for how growth arrest is regulated by SC1.
Chittka
Alexandra
A
Institute for Clinical Neurobiology, University of Würzburg, Würzburg, Germany. a.chittka@ich.ucl.ac.uk
Arevalo
Juan Carlos
JC
Rodriguez-Guzman
Maria
M
Pérez
Pilar
P
Chao
Moses V
MV
Sendtner
Michael
M
D016475:3T3 Cells; D000818:Animals; D002135:Calcium-Binding Proteins; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D019927:Cyclin E / Q000235:genetics*; D016326:Extracellular Matrix Proteins; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics; D016335:Zinc Fingers
D002135:Calcium-Binding Proteins; D019927:Cyclin E; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D012097:Repressor Proteins; C489290:SC1 protein, mouse; C503128:Sparcl1 protein, rat