The integrin interacts with cki-1/p27kip1, a tumor suppressor gene, of the nematode Caenorhabditis elegans.




Yu, Eun-Jeong.

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Integrin is a heterodimeric cell surface receptor for extracellular matrix (ECM) and plays essential roles in regulating cell behaviors such as cell migration, adhesion, growth and death. The cell-ECM interaction is particularly important for progression and arrest of cell cycle. However, the mechanism by which the ECM influences the cell cycle in vivo is poorly understood. To study the role of integrin in cell cycle, we generated a pat-3, Caenorhabditis elegans β integrin, transgenic mutant. The pat-3 (sp) carrying a defective splicing of intron 7 displayed growth defective phenotypes such as coldsensitive larval arrest, shorter body length, reduced lifespan, and increased sterility. To study the role of integrin in cell growth, we assessed for the interaction of integrin signaling to CKI-1 that is a C. elegans homologue of the cyclin dependent kinase inhibitor p27kip1, a tumor suppressor. In wild type pat-3 (+), CKI-1::GFP is localized to nucleoli in hypodermis; whereas, CKI-1::GFP appeares clumped and scattered in the nucleoplasm of pat-3 (sp). In addition, the level of CKI-1::GFP protein was found elevated in pat-3 (sp). In an RNAi screen, we found that integrin signaling and SCF E3 ubiquitin ligase genes appeared to involve in the localization and expression of CKI-1. This result suggests that integrin signaling and SCF E3 ligase work together to regulate the cellular distribution of CKI-1. We continued to study the localization of CKI-1 and investigate suppressors of pat-3 (sp) defects. RNAi screen revealed that genes involved in ribosome biogenesis, unfolded protein response, chromatin modification, rRNA processing, and ubiquitin-mediated protein degradation are required for the up regulation of CKI-1::GFP, suggesting that integrin signaling links to the function of many genes acting in nucleus, nucleolus, and protein degradation. My study demonstrated that integrin plays robust roles in regulating the proper localization and level of CKI-1/p27kip1 in concert with integrin signaling, protein degradation, and many nucleus expressed genes including dnc-1, hda-1, mig-32, and lpd- 7. This provides insight into potential molecular mechanism of the mammalian β1 integrin splice variants, β1B and β1C, in regulating cell behavior.



Caenorhabditis elegans., Integrin., Cell cycle., Nucleolus., Tumor suppressor gene.