407회 다운증후군 중요부위 유전자1 (DSCR1)의 신경세포 분화와 사멸 과정에서의 신호전달기전

407회

연사 : 서 수 련, 강원대학교 분자생명과학과

제목 : 다운증후군 중요부위 유전자1 (DSCR1)의 신경세포 분화와 사멸 과정에서의 신호전달기전.

ABSTRACT

Down Syndrome (DS) is the most common genetic cause of mental retardation. Most DS patients develop early-onset Alzheimer disease (AD) neuropathology, including amyloid-β deposition and neurofibrillay tangles. Down Syndrome Critical Region 1 (DSCR1) located on chromosome 21 is overexpressed in the brain of Down syndrome (DS) fetus and encodes an inhibitor of phosphatase, calcineurin, which might be a key factor in AD and play a role in learning and memory. Overexpression of DSCR1 in cells inhibits calcineurin activity and related downstream signaling. It is known that DSCR1 is highly expressed in heart and brain. However, regulatory mechanism of DSCR1 expression in neuronal cells has not been well addressed. Therefore, we initiated the present study to determine neuronal function of DSCR1 and its regulation. Here we show that an elevation of intracellular cAMP by forskolin increases the steady-state level of DSCR1 through a phosphorylation of protein kinase A (PKA) in neuronal cells. Furthermore, DSCR1 could be directly phosphorylated by PKA in vitro and this action was blocked by PKA specific inhibitors. Consistent with this notion, phosphatase inhibitor, but not calcineurin inhibitors, enhanced the accumulation of DSCR1, indicating that DSCR1 phosphorylation is involved for its increased stability. In addition, deletion analysis revealed that C-terminal domain of DSCR1 is responsible for forskolin-induced protein accumulation. Taken together, our findings suggest that cAMP-mediated DSCR1 phosphorylation protects the protein from being degraded by proteasome, thereby modulating its functional activity in neurological disorder, DS.