title: Moesin-ezrin-radixin-like protein (merlin) mediates protein interacting with the carboxyl terminus-1 (PICT-1)-induced growth inhibition of glioblastoma cells in the nucleus.
abstract: Moesin-ezrin-radixin-like protein (merlin) has long been considered a unique tumour suppressor that inhibits mitogenic signalling only at the membrane-cytoskeleton interface. However, the nucleocytoplasmic shuttling of merlin in a cell cycle-dependent manner has recently been observed, indicating that merlin may also exert its tumour-suppressive activity by interacting with specific nuclear protein partners. We have identified protein interacting with carboxyl terminus 1 (PICT-1) as a novel merlin-binding partner. Although the detailed mechanisms are not fully understood, several lines of evidence have previously implicated PICT-1 as a candidate tumour suppressor, including its phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-dependent growth-suppression and cell-killing activities. We show here that PICT-1 is localised to the nucleolus, and Ser518-dephosphorylated merlin (the growth-inhibitory form of merlin) can interact with PICT-1 in the nucleolus. Ectopic expression of PICT-1, both in PTEN-positive HeLa cells and in PTEN-deficient U251 cells, effectively represses cyclin D1 expression, arrests the cell cycle at G0/G1, and promotes cell apoptosis. PICT-1 (1-356), a carboxyl-terminus truncated mutant that has lost the ability to bind merlin, has a markedly reduced inhibitory effect on the cell cycle and proliferation. Knockdown of merlin expression by siRNA attenuates the inhibitory effects induced by PICT-1 over-expression. We propose that merlin mediates PICT-1-induced growth inhibition by translocating to the nucleolus and binding PICT-1.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Lanzhen
authors.initials: L
authors.lastname: Zhou
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.forename: Caiping
authors.initials: C
authors.lastname: Guo
authors.forename: Junchang
authors.initials: J
authors.lastname: Li
authors.forename: Huixia
authors.initials: H
authors.lastname: Wang
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Laiqiang
authors.initials: L
authors.lastname: Huang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D025581:Neurofibromin 2 / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016192:Resting Phase, Cell Cycle; D012694:Serine / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C500712:NOP53 protein, human; D025581:Neurofibromin 2; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D012694:Serine