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조재형 (Jaehyung Cho) 저자 이메일 보기
University of Illinois-Chicago College of Medicine
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조회 914  인쇄하기 주소복사 트위터 공유 페이스북 공유 
DREAM plays an important role in platelet activation and thrombogenesis

Kyungho Kim,1 Alan Tseng,1 Andrew Barazia,1 Joseph E. Italiano,2 and Jaehyung Cho1,*

Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612
2 Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

*Correspondence: Jaehyung Cho, Ph.D.

Downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor, is known to modulate pain responses. However, it is unknown whether DREAM is expressed in anucleate platelets and plays a role in thrombogenesis. By using intravital microscopy with DREAM-null mice and their bone marrow chimeras, we demonstrated that both hematopoietic and non-hematopoietic cell DREAM are required for platelet thrombus formation following laser-induced arteriolar injury. In a FeCl3-induced thrombosis model, we found that compared to WT control and non-hematopoietic DREAM knockout (KO) mice, DREAM KO control and hematopoietic DREAM KO mice showed a significant delay in time to occlusion. Tail bleeding time was prolonged in DREAM KO control mice, but not WT or DREAM bone marrow chimeric mice. In vivo adoptive transfer experiments further indicated the importance of platelet DREAM in thrombogenesis. We found that DREAM deletion does not alter the ultrastructural features of platelets but significantly impairs platelet aggregation and ATP secretion induced by numerous agonists (collagen-related peptide (CRP), ADP, A23187, thrombin, or U46619). Biochemical studies revealed that platelet DREAM positively regulates phosphoinositide 3-kinase (PI3K) activity during platelet activation. Using DREAM-null platelets and PI3K isoform-specific inhibitors, we observed that platelet DREAM is important for α-granule secretion, Ca2+ mobilization, and aggregation through PI3K class Iβ (PI3K-Iβ). Genetic and pharmacological studies in human megakaryoblastic MEG-01 cells showed that DREAM is important for A23187-induced Ca2+ mobilization and its regulatory function requires Ca2+ binding and PI3K-Iβ activation. These results suggest that platelet DREAM regulates PI3K-Iβ activity and plays an important role during thrombus formation.

- 형식: Research article
- 게재일: 2016년 11월 (BRIC 등록일 2016-12-06)
- 연구진: 국외연구진
- 분야: Medicine
Dot/Icm 제 4 유형 커플링 단백질 복합체의 선택적 이펙터 단백질 인식[Nat. Commun.]
발표: 김현민 (KAIST)
일자: 2020년 9월 29일 (화) 오후 02시 (한국시간)
언어: 한국어
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발표: 이소아 (Stanford Cardiovascular...)
일자: 2020년 10월 8일 (목) 오후 02시 (한국시간)
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