한빛사
>
한빛사논문
한빛사논문
1
- 조회3,940
Nature, Published online 06 January 2016, 529, 172-177 | doi:10.1038/nature16475
An ID2-dependent mechanism for VHL inactivation in cancer
Abstract
Sang Bae Lee1, Veronique Frattini1, Mukesh Bansal2,3, Angelica M. Castano1, Dan Sherman4, Keino Hutchinson4, Jeffrey N. Bruce5, Andrea Califano2,3, Guangchao Liu1, Timothy Cardozo4, Antonio Iavarone1,6,7 & Anna Lasorella1,7,8
1Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA. 2Department of Systems Biology, Columbia University Medical Center, New York 10032, USA. 3Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York 10032, USA. 4Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York 10014, USA. 5Department of Neurosurgery, Columbia University Medical Center, New York 10032, USA. 6Department of Neurology, Columbia University Medical Center, New York 10032, USA. 7Department of Pathology, Columbia University Medical Center, New York 10032, USA. 8Department of Pediatrics, Columbia University Medical Center, New York 10032, USA.
Correspondence to : Anna Lasorella or Antonio Iavarone
Abstract
Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma, ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.
논문정보
- Research article
- 2016년 01월 (BRIC 등록일 2016-01-19)
- 국외 연구진
- 생명과학 > 분자생물학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
