Apoptotic histone modification inhibits nuclear transport by regulating RCC1.
A number of signalling pathways have been identified that regulate apoptosis, but the mechanism that initiates apoptosis remains incompletely understood. We have found that the nuclear RanGTP level is diminished during the early stages of apoptosis, which correlates with immobilization of RCC1 on the chromosomes. Furthermore, the expression of phosphomimetic histone H2B or caspase-activated Mst1 immobilizes RCC1 and causes reduction of nuclear RanGTP levels, which leads to inactivation of the nuclear transport machinery. As a consequence, nuclear localization signal (NLS)-containing proteins, including NF-kappaB-p65, remain bound to importins alpha and beta in the cytoplasm. Knocking down Mst1 allows resumption of nuclear transport and the nuclear entry of NF-kappaB-p65, which have important roles in rescuing cells from apoptosis. Therefore, we propose that RCC1 reads the histone code created by caspase-activated Mst1 to initiate apoptosis by reducing the level of RanGTP in the nucleus.
Wong
Chi-Hang
CH
Division of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore 637551.
Chan
Hei
H
Ho
Chin-Yee
CY
Lai
Soak-Kuan
SK
Chan
Kheng-Sze
KS
Koh
Cheng-Gee
CG
Li
Hoi-Yeung
HY
D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D020931:ran GTP-Binding Protein; C062521:RCC1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases