HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins.
Human enhancer of invasion, clone 10 (HEI10) (CCNB1IP1) was first described as a RING-finger family ubiquitin ligase that regulates cell cycle by interacting with cyclin B and promoting its degradation. Subsequently, other studies suggested specific upregulation of HEI10 in metastatic melanoma and demonstrated direct interaction between HEI10 and the tumor suppressor Merlin, encoded by the neurofibromatosis 2 gene. These and other results led us to hypothesize that HEI10 also influences the processes of cell migration and metastasis. We here show that cells with depleted HEI10 both migrate more rapidly and invade more effectively than control cells. HEI10 depletion post-transcriptionally increases the expression of a group of promotility regulatory proteins including p130Cas, paxillin, Cdk1 and cyclin B2, but excluding Merlin. Among these, only inhibition of Cdk1/cyclin B activity specifically reversed the motility and invasion of HEI10-depleted cells. Finally, HEI10 is abundantly transcribed in many human tissues, and particularly abundant in some tumor cell lines, suggesting that it may be commonly involved in coordinating cell cycle with cell migration and invasion.
Singh
M K
MK
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Nicolas
E
E
Gherraby
W
W
Dadke
D
D
Lessin
S
S
Golemis
E A
EA
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008856:Microscopy, Fluorescence; D051419:Paxillin / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077546:Roscovitine; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C493841:BCAR1 protein, human; D018797:Cell Cycle Proteins; D050719:Crk-Associated Substrate Protein; D019926:Cyclin B; D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D000077546:Roscovitine; C473026:CCNB1IP1 protein, human; D044767:Ubiquitin-Protein Ligases; D016203:CDC2 Protein Kinase; D020764:cdc42 GTP-Binding Protein; D002945:Cisplatin