ets-2 Is a Target for an Akt (Protein Kinase B)/Jun N-Terminal Kinase Signaling Pathway in Macrophages of <i>motheaten-viable</i> Mutant Mice

Smith, James L.; Schaffner, Alicia E.; Hofmeister, Joseph K.; Hartman, Matthew Hartman; Guo, Wei; Forsthoefel, David J.; Hume, David; Ostrowski, Michael C.

doi:10.1128/mcb.20.21.8026-8034.2000

Cited by 67 publications

(66 citation statements)

References 53 publications

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“…Maximum induction was observed 1 h after addition of PMA, which is 1 h before the peak level of PTHrP P3-specific transcript in response to PMA was reached ( Figure 1C). To activate the Ets2 protein, PMA could trigger phosphorylation at Thr 72 [33] by stimulating either the Raf/MEK-1/ERK1/2 or the phosphoinositide 3-kinase pathway [33,44]. As shown in Figures 1(D) and 2(B), we have already demonstrated that MEK-1 inhibitor PD98059 inhibits PMAinduced P3-dependent PTHrP expression and P3-dependent transcription.…”

Section: Pma Modulates Ets2 Activity In Mcf-7 Cellsmentioning

confidence: 64%

Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

Lindemann

Braig

Hauser

et al. 2003

Biochemical Journal

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Parathyroid hormone-related protein (PTHrP) promotes the metastatic potential and proliferation of breast cancer cells, and acts anti-apoptotically. In invasive MDA-MB-231 breast cancer cells, transforming growth factor β-regulated PTHrP synthesis is mediated by an Ets1/Smad3-dependent activation of the PTHrP P3 promoter. In the present study, we studied the regulation of PTHrP expression in non-invasive, Ets1-deficient and transforming growth factor β-resistant MCF-7 cells. We found PMA to be a strong stimulator of P3-dependent PTHrP expression in MCF-7 cells. Mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase 1 (MEK-1)/ERK1/2 inhibitor PD98059 interfered with this activity. Promoter studies revealed that the PMA effect depended on the Ets and stimulating protein-1 (Sp1)-binding sites. Of several Ets factors tested, Ets2, but not Ese-1, Elf-1 or Ets1, supported the PMA-dependent increase in promoter activity. PD98059 and a threonine to alanine mutation of the ERK1/2-responsive Ets2 phosphorylation site at position 72 inhibited the Ets2/PMA effect. Activated protein kinase C (PKC)ε could mimic PMA by stimulating the P3 promoter alone or in co-operation with Ets2 in an MEK-1/ERK1/2-dependent manner. Activated PKCα, although capable of co-operating with Ets2, failed to induce transcription from the P3 promoter on its own. The Ets2/PKCα synergistic effect was neither sensitive to PD98059 nor to Thr 72 /Ala 72 mutation. PMA neither increased the expression of Sp1 nor modulated the transcriptional activity of Sp1. However, it induced the displacement of a yet unknown factor from the Sp1-binding site, which may result in Sp1 recruitment to the promoter. Our results suggest an ERK1/2-dependent Ets2/PKCε synergism to be involved in PTHrP expression in MCF-7 breast cancer cells.

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Section: Pma Modulates Ets2 Activity In Mcf-7 Cellsmentioning

confidence: 64%

Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

Lindemann

Braig

Hauser

et al. 2003

Biochemical Journal

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“…Despite the ability of U0126 to reduce phospho-ERK to control levels, and the clear efficacy of SB203580 in preventing the G2 arrest, p21 CIP1 expression was only partially inhibited by the combination of these drugs, suggesting that other pathways may also be important. Indeed, JNK can phosphorylate and activate Ets-2, c-Jun, JunB and ATF2, all of which have been proposed as regulators of the p21 CIP1 promoter (Kardassis et al, 1999;Smith et al, 2000). Unfortunately the lack of selective inhibitors of either JNK or p38g/d prevents us from further investigating the relationship between p21 CIP1 expression and SAPK activation at present.…”

Section: Discussionmentioning

confidence: 99%

ΔMEKK3:ER* activation induces a p38α/β2-dependent cell cycle arrest at the G2 checkpoint

et al. 2002

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“…ERK1/2 phosphorylates Ets-1 at Thr38 and Ets-2 at Thr72, which increases their transactivational activity (26,27). A recent study of macrophages in motheaten-viable mice showed that Thr72 of Ets-2 is phosphorylated and activated by Akt-mediated Jun-N-terminal kinase (43). Akt also induces transcriptional activity of an Ets family member, PU.1, by phosphorylating a residue in its transactivation domain (44).…”

Section: Sustained Activation Of Erk1/2 Enhances Cell Survival By Accmentioning

confidence: 99%

EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

Phuchareon

McCormick

Eisele

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.nonsmall cell lung cancer | EGFR inhibition | tyrosine kinase inhibitors | ERK1/2 paradoxical activation | innate drug resistance

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ets-2 Is a Target for an Akt (Protein Kinase B)/Jun N-Terminal Kinase Signaling Pathway in Macrophages of motheaten-viable Mutant Mice

Cited by 67 publications

References 53 publications

Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

ΔMEKK3:ER* activation induces a p38α/β2-dependent cell cycle arrest at the G2 checkpoint

EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

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