Reversible G1 Arrest Induced by Inhibition of the Epidermal Growth Factor Receptor Tyrosine Kinase Requires Up-regulation of p27KIP1 Independent of MAPK Activity

Busse, Dagmar; Doughty, Rachel S.; Ramsey, Timothy T.; Russell, William E.; Price, James O.; Flanagan, W. Michael; Shawver, Laura K.; Arteaga, Carlos L.

doi:10.1074/jbc.275.10.6987

Cited by 185 publications

(125 citation statements)

References 54 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Although the Ras/MAPK/ERK pathway has been proposed as the major mitogenic signalling pathway initiated by erbB1 activation (Malumbres and Pellicer, 1998), the fact that TGFa-induced activation of ERK was unaltered following blockade of the PI3K/Akt pathway and vice versa rules out eventual reciprocal modulations of these pathways. Our results raise the possibility that each pathway intervenes at different steps of the cell cycle, a possibility supported by studies of TGFa mitogenic effects in epithelial cell lines, where Akt stimulation is required for G1/S transition (Busse et al, 2000;Justman and Clinton, 2002). Altogether, our results show that the mobilization of both MAPK/ERK and PI3K/Akt transduction pathways are required for TGFa to exert its full mitogenic and pro-survival effects.…”

Section: Discussionsupporting

confidence: 77%

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

et al. 2006

View full text Add to dashboard Cite

Astrocyte death has been implicated in several neuropathological diseases, but the identification of molecules susceptible of promoting astrocyte survival has been elusive. We investigated whether transforming growth factor alpha (TGFa), an erbB1/EGFR ligand, which promotes glioma progression and affects astrocyte metabolism at embryonic and adult stages, regulates astrocyte survival. Primary serum-free astrocyte cultures from postnatal mouse and fetal human cortices were used. Transforming growth factor alpha protected both species of astrocytes from staurosporine-induced apoptosis. In serum-free medium, mouse astrocytes did not survive beyond 2 months while TGFa-treated astrocytes survived up to 12 months. Transforming growth factor alpha also promoted long-term survival of human astrocytes. We additionally extended TGFa proliferative effects to human astrocytes. After 3 days of permanent application, TGFa induced a major downregulation of both erbB1 and erbB2. This downregulation did not impair the functional activation of the receptors, as ascertained by their tyrosine phosphorylation and the continuous stimulation of both ERK/MAPK and PI3K/Akt pathways up to 7 days, the longest time examined. The full cellular effects of TGFa required activation of both transduction pathways. Enhanced proliferation and survival thus define TGFa as a gliatrophin for mammalian astrocytes. These results demonstrate that in normal, non-transformed astrocytes, sustained and functional erbBs activation is achieved without bypassing ligand-induced receptors downregulation.

show abstract

Section: Discussionsupporting

confidence: 77%

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Blocking EGFR signalling has been shown to stabilise the cyclindependent kinase inhibitor p27 KIP1 and leads to G 1 cell cycle arrest (Busse et al, 2000;Di Gennaro et al, 2003). PKI166 alone, and in combination with U0126 reduced ERK1/2 activity, and induced p27 KIP1 expression in SUM149 cells.…”

Section: Discussionmentioning

confidence: 99%

“…One explanation is that additional signalling pathways, insensitive to either PKI166 or U0126, were maintaining the viability of the cells. The phosphoinositide 3-kinase (PI3K) pathway is sensitive to EGFR-signalling blockade, promoting cell death through inhibition of AKT (Busse et al, 2000;Anderson et al, 2001;Moasser et al, 2001;Clark et al, 2002). PKI166 reduced basal levels of AKT activity in SUM 149, SKBR3 and MDA-MB-468, and inhibited EGF-induced AKT activity in MDA-MB-231 cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

et al. 2004

View full text Add to dashboard Cite

One of the major targets for breast cancer therapy is the epidermal growth factor receptor (EGFR) and related receptors, which signal via different signal transduction pathways including the mitogen-activated protein kinase (MAPK) pathway. This study determined whether there is a correlation between EGFR/HER2 status and MAPK (ERK1/2) phosphorylation in breast cancer cells, and how this affects the response to an inhibitor of the receptors. Expression of EGFR, HER2 and phosphorylated ERK1/2 were measured by immunoblotting in a panel of breast cancer cell lines. Several lines expressed high levels of pERK1/2, with no obvious correlation with the level of EGFR/HER2. The EGFR tyrosine kinase inhibitor PKI166 inhibited growth and induced apoptosis in some cells with high levels of growth factor receptors (MDA-MB-468, SUM149, SKBR3), but was less effective in cells that also had high basal ERK1/2 activity (MDA-MB-231). The combination of an inhibitor of MAPK signalling (U0126) and PKI166 produced significantly more inhibition and apoptosis than either agent alone. This suggests that constitutive activation of the MAPK pathway may bypass inhibition of EGFR/HER2 tyrosine kinases, and lead to insensitivity to agents targeting the receptors. However, inhibiting both EGFR/ HER2 and MAPK signalling can result in significant growth inhibition and apoptosis of EGFR-expressing breast cancer cells.

show abstract

“…38 PD098509 inhibited MEK without arresting growth of some cancer cells. 39 Thus, whereas this agent inhibits MEK at low micromolar concentrations, it does not inhibit proliferation of SKBr3 cells 40 and HL60 cells, 37,41 unless 60-100 µM concentrations of PD098509 were used.…”

Section: Inhibitors Of Mitogenic Kinases and Autonomous Growthmentioning

confidence: 99%

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Blagosklonny¹,

Darżynkiewicz²

2002

Cell Cycle

View full text Add to dashboard Cite

Avoidance of apoptosis and mitogen-independent growth are hallmarks of cancer. Mitogen-activated kinases (for example, ErbB1, Raf-1, MEK, PI-3-K, mTOR) can suppress chemotherapy-induced apoptosis in cancer cells. While kinase inhibitors restore susceptibility of cancer cells to apoptosis, they do not necessarily cause growth arrest in cancer cells harboring additional mutations in downstream signaling pathways such as inactivation of Rb and overexpression of c-myc. This article provides a conceptual basis for a novel use of inhibitors of mitogenic kinases. While arresting growth of normal cells, kinase inhibitors may not arrest cancer cells but instead can sensitize them to apoptosis. Following pretreatment with low doses of kinase inhibitors, the chemotherapy that predominantly induces apoptosis in cycling cells (cyclotherapy) will kill cancer cells while sparing normal cells.

show abstract

Reversible G1 Arrest Induced by Inhibition of the Epidermal Growth Factor Receptor Tyrosine Kinase Requires Up-regulation of p27KIP1 Independent of MAPK Activity

Cited by 185 publications

References 54 publications

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Contact Info

Product

Resources

About