HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins

Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Oncogene (Impact Factor: 8.46). 08/2007; 26(33):4825-32. DOI: 10.1038/sj.onc.1210282
Source: PubMed


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.

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    • "In addition to cNCC migration related factors, many cell cycle related genes are differentially expressed in Wnt1-Cre Hand2 CKOs (Holler et al., 2010). The most highly regulated of these genes (up 37 fold) was cyclin B1 interacting protein 1 (Ccnb1ip1), which is an ubiquitin ligase that promotes the degradation of cyclin B. While the details of its function during development remain unclear, recent malignancy related research suggests that Ccnb1ip1 plays a role in coordinating the cell cycle with cell migration and invasion (Singh et al., 2007)—functions required for OFT septation and valve formation . Others included cdk6, a serine/threonine kinase that regulates the G0 to G1 transition by phosphorylating retinoblastoma protein (pRb) (Malumbres and Barbacid, 2005), Insm1, a regulator of NCC derived sympathetic neuron development which also interacts with cyclin D1 in the heart (Liu et al., 2006; Pellegrino et al., 2011), and several histones. "
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