Role of beta2-chimaerin in the behaviour of murine mammary carcinoma cells in response to extracellular matrix components.
Chimaerins are high affinity receptors for phorbol esters and diacylglycerol (DAG), unrelated to the protein kinase C isozymes. These receptors have deep implications in tumour biology since they regulate the activity of Rac1, a small GTP-binding protein of the Ras superfamily. It has been demonstrated that chimaerins have GTPase activating protein (GAP) activity, leading to the acceleration of GTP hydrolysis from Rac1 and therefore facilitating the transition to its inactive state. Rac regulates various cellular events, including gene transcription, cell cycle, adhesion and migration. It has also been described that Rac is implicated in the intracellular response to the binding of specific extracellular matrix proteins to integrin receptors. In this work, we analysed cell morphology, actin cytoskeleton reorganisation and metalloprotease (MMP) secretion in response to matrix proteins in mouse mammary carcinoma cells transfected with the beta2-chimaerin GAP domain. Overexpression of beta2-chimaerin induced important cytoskeletal rearrangements in response to matrix stimuli. Transfectant cells also showed activation of MMP-9 activity after stimulation with collagen IV and epidermal growth factor. The restitution of normal Rac levels by beta2-chimaerin activity induced an increase in the sensitivity of tumour cells to extracellular factors, suggesting a regression of the malignant phenotype.
Menna
Pablo Lorenzano
PL
Laboratory of Molecular Oncology, Quilmes National University, Buenos Aires, Argentina.
Peche
Leticia Y
LY
Alonso
Daniel F
DF
Gomez
Daniel E
DE
D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism*; D005353:Fibronectins / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000199:Actins; D024141:Collagen Type IV; D005353:Fibronectins; D009363:Neoplasm Proteins; C079844:beta-chimaerin; D004815:Epidermal Growth Factor; D020780:Matrix Metalloproteinase 9