Abstract
In cellular transformation, activated forms of the small GTPases Ras and RhoA can cooperate to drive cells through the G1 phase of the cell cycle. Here, we show that a similar but substrate-regulated mechanism is involved in the anchorage-dependent proliferation of untransformed NIH-3T3 cells. Among several extracellular matrix components tested, only fibronectin supported growth factor-induced, E2F-dependent S phase entry. Although all substrates supported the mitogen-activated protein kinase (MAPK) response to growth factors, RhoA activity was specifically enhanced on fibronectin. Moreover, induction of cyclin D1 and suppression of p21(Cip/Waf) occurred specifically, in a Rho-dependent fashion, in cells attached to fibronectin. This ability of fibronectin to stimulate both Ras/MAPK- and RhoA-dependent signaling can explain its potent cooperation with growth factors in the stimulation of cell cycle progression.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Actins / metabolism
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Animals
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Carrier Proteins*
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Cell Adhesion
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Cell Cycle / drug effects*
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Cell Cycle Proteins*
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Culture Media, Serum-Free
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / antagonists & inhibitors
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Cyclins / genetics
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Cyclins / metabolism
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Cytoskeleton / metabolism
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DNA-Binding Proteins*
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E2F Transcription Factors
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Enzyme Activation
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Fibronectins / metabolism*
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G1 Phase
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Growth Substances / pharmacology*
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Mice
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Mitogen-Activated Protein Kinases / metabolism*
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Models, Biological
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Retinoblastoma Protein / metabolism
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Retinoblastoma-Binding Protein 1
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S Phase
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Signal Transduction / drug effects
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Transcription Factor DP1
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Transcription Factors / metabolism
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Transfection
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ras GTPase-Activating Proteins / metabolism*
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rhoA GTP-Binding Protein / metabolism*
Substances
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Actins
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Arid4a protein, mouse
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Carrier Proteins
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Cdkn1a protein, mouse
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Cell Cycle Proteins
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Culture Media, Serum-Free
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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E2F Transcription Factors
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Fibronectins
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Growth Substances
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RNA, Messenger
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Retinoblastoma Protein
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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ras GTPase-Activating Proteins
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Cyclin D1
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Mitogen-Activated Protein Kinases
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rhoA GTP-Binding Protein