Ph.D. Dept. of Human Genetics, Yale University
Centriole Duplication, Neural Stem Cell Division, and Tumorigenesis
The centriole is an essential component of the centrosome, which is required for the formation of the mitotic spindle, cilia, and flagella. Centriole duplication involves the growth of a procentriole (daughter centriole) from an existing centriole (mother centriole). Primary microcephaly (MCPH) is characterized by a substantial reduction in size of the cerebral cortex with mild to severe mental retardation. Recent studies from many laboratories have reported that mutations in the CPAP/CENPJ, STIL, and CEP135 genes cause MCPH, but the molecular details were not fully elucidated. During the past years, my laboratory has identified the roles of three human microcephaly proteins, CPAP, STIL, and CEP135, and two previously uncharacterized centriolar proteins, CEP120 and CEP295 in centriole duplication. We found that CPAP plays key roles in the regulation of centriole duplication and in the control of centriole length (Nat Cell Biol., 2009). We further demonstrated that CPAP could interact and form separate complexes with STIL (EMBO J., 2011), CEP135 (EMBO J., 2013), and CEP120 (J. Cell Biol. 2013), and that these interactions are critical for centriole duplication. In addition, CPAP could maintain centrosome integrity through its phosphorylation by Aurora-A during mitosis (Cell Reports 2016). Recent reports showed that genomic instability is a characteristic of most cancers and uncontrolled centriole/centrosome replication might lead to unrestrained proliferation and cause chromosome instability in cancers. My lab is now working on the molecular control of centriole/centrosome duplication, the roles of centrosomes in the pathological effects of primary microcephaly and tumorigenesis.
細胞中心體含有母、子二顆中心粒，主要是促成細胞纖毛，鞭毛的形成及參與細胞有絲分裂。畸型小頭症（MCPH）是一種人類遺傳疾病，主要症狀是病人腦容量小，並伴隨中，重度智力障礙。目前已知至少有12種MCPH基因缺陷會造成畸型小頭症。近年來本研究室解開三個畸型小頭症蛋白CPAP, STIL及CEP135的功能。發現STIL（EMBO J, 2011)， CEP135 (EMBO J, 2013) 都會與CPAP蛋白（Nat. Cell Biol. 2009）結合，形成一個蛋白質複合體，共同參與中心粒的複製與生成。據此我們提出一個假設：干擾細胞中心粒複製，將會抑制神經幹細胞分裂與減少大腦皮層神經細胞數目，繼而造成人類畸型小頭症。另外本研究室亦發現CEP120 (J Cell Biol, 2013)與CEP295 (J Cell Sci 2016)蛋白會調節中心粒長度，且在有絲分裂時CPAP蛋白會受Aurora-A激酶磷酸化，進而調節中心體的功能 (Cell Reports 2016)。近年來癌細胞發現有基因體不穩定現象，此有可能是中心體複製不正常所致。本研究室主要是研究探討中心體/中心粒複製分子機轉，及干擾此機轉所可能誘發畸型小頭症及癌基因體不穩定之原因。