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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Available from: Erica A Golemis
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    • "Hei10 was originally identified as a growth regulatory gene (Toby et al. 2003). It is hyperexpressed in certain cancer cells (Singh et al. 2007) but paradoxically can also constrain cancer proliferation (Singh et al. 2007; Scoles 2008). Sequence inspection identifies determinants that specify E3 ligase activity and SUMO binding (and thus post-translational modification via ubiquitin/SUMO) and both cyclin binding and cyclin-dependent kinase (CDK) phosphorylation (and thus interplay with the cell cycle) (Supplemental Fig. 1). "
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    ABSTRACT: Human enhancer of invasion-10 (Hei10) mediates meiotic recombination and also plays roles in cell proliferation. Here we explore Hei10's roles throughout the sexual cycle of the fungus Sordaria with respect to localization and effects of null, RING-binding, and putative cyclin-binding (RXL) domain mutations. Hei10 makes three successive types of foci. Early foci form along synaptonemal complex (SC) central regions. At some of these positions, depending on its RING and RXL domains, Hei10 mediates development and turnover of two sequential types of recombination complexes, each demarked by characteristic amplified Hei10 foci. Integration with ultrastructural data for recombination nodules further reveals that recombination complexes differentiate into three types, one of which corresponds to crossover recombination events during or prior to SC formation. Finally, Hei10 positively and negatively modulates SUMO localization along SCs by its RING and RXL domains, respectively. The presented findings suggest that Hei10 integrates signals from the SC, associated recombination complexes, and the cell cycle to mediate both the development and programmed turnover/evolution of recombination complexes via SUMOylation/ubiquitination. Analogous cell cycle-linked assembly/disassembly switching could underlie localization and roles for Hei10 in centrosome/spindle pole body dynamics and associated nuclear trafficking. We suggest that Hei10 is a unique type of structure-based signal transduction protein.
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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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    • "Ccnb1ip1 encodes a coiled-coil RING domain-containing protein, whereas Ccnb1ip1mei4 bears a donor splice site mutation resulting in an aberrantly spliced transcript [3]. Studies of CCNB1IP1 in cultured somatic cells implicated a role for this putative ubiquitin E3 ligase in Cyclin B regulation, cell cycle progression, and cell invasion [5,6]. However, the exact function of CCNB1IP1 in meiotic recombination remains is unclear. "
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