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Vol. 12, Issue 3, 725-738, March 2001
Institut National de la Santé et de la Recherche
Médicale U522, Unité de Recherches Hépatologiques,
Institut Fédératif de Recherche 97, Hôpital
Pontchaillou, 35033 Rennes, France; and Cell shape plays a role in cell growth, differentiation, and death.
Herein, we used the hepatocyte, a normal, highly differentiated cell
characterized by a long G1 phase, to understand the mechanisms that link cell shape to growth. First, evidence was provided that the
mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) cascade is a key transduction pathway controlling the hepatocyte morphology. MEK2/ERK2 activation in early G1
phase did not lead to cell proliferation but induced cell shape
spreading and demonstration was provided that this MAPK-dependent
spreading was required for reaching G1/S transition and DNA
replication. Moreover, epidermal growth factor (EGF) was found to
control this morphogenic signal in addition to its mitogenic effect.
Thus, blockade of cell spreading by cytochalasin D or PD98059 treatment
resulted in inhibition of EGF-dependent DNA replication. Our data led
us to assess the first third of G1, is exclusively devoted to the
growth factor-dependent morphogenic events, whereas the mitogenic
signal occured at only approximately mid-G1 phase. Moreover,
these two growth factor-related sequential signaling events involved
successively activation of MEK2-ERK2 and then MEK1/2-ERK1/2 isoforms.
In addition, we demonstrated that inhibition of extracellular matrix
receptor, such as integrin U456, Faculté de
Médecine, 35033 Rennes, France
1 subunit, leads to cell arrest
in G1, whereas EGF was found to up-regulated integrin 1 and
fibronectin in a MEK-ERK-dependent manner. This process in relation to
cytoskeletal reorganization could induce hepatocyte spreading, making
them permissive for DNA replication. Our results provide new insight
into the mechanisms by which a growth factor can temporally control
dual morphogenic and mitogenic signals during the G1 phase.
Corresponding author. E-mail
address: georges.baffet{at}rennes.inserm.fr.
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