Mutant alpha-actinin-4 promotes tumorigenicity and regulates cell motility of a human lung carcinoma.
The precise role of alpha-actinin-4 encoding gene (ACTN4) is not very well understood. It has been reported to elicit tumor suppressor activity and to regulate cellular motility. To further assess the function of human ACTN4, we studied a lung carcinoma cell line expressing a mutated alpha-actinin-4, which is recognized as a tumor antigen by autologous CD8(+) cytotoxic T lymphocytes (CTL). Confocal immunofluorescence microscopy indicated that, while wild-type (WT) alpha-actinin-4 stains into actin cytoskeleton and cell surface ruffles, the mutated protein is only dispersed in the cytoplasm of the lung carcinoma cells. This loss of association with the cell surface did not appear to correlate with a decrease in in vitro alpha-actinin-4 crosslinking to filamentous (F)-actin. Interestingly, experiments using cell lines stably expressing ACTN4 demonstrated that as opposed to WT gene, mutant ACTN4 was unable to inhibit tumor cell growth in vitro and in vivo. Moreover, the expression of mutant alpha-actinin-4 resulted in the loss of tumor cell capacity to migrate. The identification of an inactivating mutation in ACTN4 emphasizes its role as a tumor suppressor gene and underlines the involvement of cytoskeleton alteration in tumor development and metastasis.
Menez
Jeanne
J
Laboratoire Cytokines et Immunologie des tumeurs Humaines, U487 INSERM, Institut Fédératif de Recherche 54, Institut Gustave Roussy, F-94805 Villejuif Cedex, France.
Le Maux Chansac
Béatrice
B
Dorothée
Guillaume
G
Vergnon
Isabelle
I
Jalil
Abdelali
A
Carlier
Marie-France
MF
Chouaib
Salem
S
Mami-Chouaib
Fathia
F
D000185:Actinin / Q000235:genetics* / Q000502:physiology*; D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017354:Point Mutation; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
C111453:ACTN4 protein, human; D000199:Actins; C491752:Actn4 protein, mouse; D018076:DNA, Complementary; D008840:Microfilament Proteins; D000185:Actinin