HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins.
ABSTRACT 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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ABSTRACT: HEI10 was first described in human as a RING domain-containing protein that regulates cell cycle and cell invasion. Mice HEI10(mei4) mutant displays no obvious defect other than meiotic failure from an absence of chiasmata. In this study, we characterize rice HEI10 by map-based cloning and explore its function during meiotic recombination. In the rice hei10 mutant, chiasma frequency is markedly reduced, and those remaining chiasmata exhibit a random distribution among cells, suggesting possible involvement of HEI10 in the formation of interference-sensitive crossovers (COs). However, mutation of HEI10 does not affect early recombination events and synaptonemal complex (SC) formation. HEI10 protein displays a highly dynamic localization on the meiotic chromosomes. It initially appears as distinct foci and co-localizes with MER3. Thereafter, HEI10 signals elongate along the chromosomes and finally restrict to prominent foci that specially localize to chiasma sites. The linear HEI10 signals always localize on ZEP1 signals, indicating that HEI10 extends along the chromosome in the wake of synapsis. Together our results suggest that HEI10 is the homolog of budding yeast Zip3 and Caenorhabditis elegans ZHP-3, and may specifically promote class I CO formation through modification of various meiotic components.PLoS Genetics 07/2012; 8(7):e1002809. · 8.69 Impact Factor
Article: Evidence Implicating CCNB1IP1, a RING Domain-Containing Protein Required for Meiotic Crossing Over in Mice, as an E3 SUMO Ligase.[show abstract] [hide abstract]
ABSTRACT: The RING domain-containing protein CCNB1IP1 (Cyclin B1 Interacting Protein 1) is a putative ubiquitin E3 ligase that is essential for chiasmata formation, and hence fertility, in mice. Previous studies in cultured cells indicated that CCNB1IP1 targets Cyclin B for degradation, thus playing a role in cell cycle regulation. Mice homozygous for a mutant allele (mei4) of Ccnb1ip1 display no detectable phenotype other than meiotic failure from an absence of chiasmata. CCNB1IP1 is not conserved in key model organisms such as yeast and Drosophila, and there are no features of the protein that implicate clear mechanisms for a role in recombination. To gain insight into CCNB1IP1's function in meiotic cells, we raised a specific antibody and determined that the protein appears in pachynema. This indicates that CCNB1IP1 is involved with crossover intermediate maturation, rather than early (leptotene) specification of a subset of SPO11-induced double strand breaks towards the crossover pathway. Additionally, a yeast 2-hybrid (Y2H) screen revealed that CCNB1IP1 interacts with SUMO2 and a set of proteins enriched for consensus sumoylation sites. The Y2H studies, combined with scrutiny of CCNB1IP1 domains, implicate this protein as an E3 ligase of the sumoylation cascade. We hypothesize CCNB1IP1 represents a novel meiosis-specific SUMO E3 ligase critical to resolution of recombination intermediates into mature chiasmata.Genes. 12/2010; 1(3):440-451.
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ABSTRACT: In numerous species, the formation of meiotic crossovers is largely under the control of a group of proteins known as ZMM. Here, we identified a new ZMM protein, HEI10, a RING finger-containing protein that is well conserved among species. We show that HEI10 is structurally and functionally related to the yeast Zip3 ZMM and that it is absolutely required for class I crossover (CO) formation in Arabidopsis thaliana. Furthermore, we show that it is present as numerous foci on the chromosome axes and the synaptonemal complex central element until pachytene. Then, from pachytene to diakinesis, HEI10 is retained at a limited number of sites that correspond to class I COs, where it co-localises with MLH1. Assuming that HEI10 early staining represents an early selection of recombination intermediates to be channelled into the ZMM pathway, HEI10 would therefore draw a continuity between early chosen recombination intermediates and final class I COs.PLoS Genetics 07/2012; 8(7):e1002799. · 8.69 Impact Factor