title: Multiple effects of curcumin on promoting expression of the exon 7-containing SMN2 transcript.
abstract: Survival of motor neuron 2 (SMN2) is a modifier gene for spinal muscular atrophy (SMA), a neurodegenerative disease caused by insufficient SMN protein mostly due to SMN1 defect. SMN2 is nearly identical to SMN1 but unfortunately only able to produce a small amount of SMN protein due to exon 7 skipping. The exon 7-containing SMN2 transcript (SMN2_E7+) can be increased by a dietary compound, curcumin, but the involved molecular changes are not clear. Here we have found that in fibroblast cells of a SMA type II patient, curcumin enhanced the inclusion of SMN2 exon 7. Examination of the potential splicing factors showed that curcumin specifically increased the protein and transcript levels of SRSF1. The increased SRSF1 protein was mainly nuclear and hyperphosphorylated. Interestingly, the curcumin effects on the SMN2 and SRSF1 transcripts were inhibited by a protein deacetylase inhibitor, trichostatin A. Moreover, in support of its role in the SMN2 splicing, knocking down SRSF1 reduced the inclusion of SMN2 exon 7. Thus, curcumin appears to have multiple effects on the SMN2 transcript and its splicing regulators, including the change of alternative splicing and transcript/protein level as well as phosphorylation. Protein deacetylases and phosphatases are likely involved in these effects. Interestingly, the effects all seem to favor production of the SMN2_E7+ transcript in SMA patient cells.
authors.affiliation: Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.|Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada.|Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada.
authors.forename: Dairong
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.|Department of Diagnostic Ultrasound, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.|Department of Pediatrics, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Pediatrics, Chinese PLA General Hospital, Beijing, 100853, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China. hsz_pumc@ibms.pumc.edu.cn.
authors.forename: Shangzhi
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada. xiej@umanitoba.ca.|Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada. xiej@umanitoba.ca.
authors.forename: Jiuyong
authors.initials: J
authors.lastname: Xie
keywords: Curcumin; Phosphorylation; SMN2; SRSF1; Splicing