Protein kinase Cα regulates Ets1 transcriptional activity in invasive breast cancer cells

Lindemann, Ralph K.; Braig, Melanie; Ballschmieter, Pia; Guise, Theresa A.; Nordheim, Alfred; Dittmer, Jürgen

doi:10.3892/ijo.22.4.799

Cited by 27 publications

(33 citation statements)

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“…Both PKC forms are expressed in MCF-7 cells [45]. To analyse the effect of these particular PKCs on P3 promoter activity, we used constitutively active forms of these kinases (PKCα-CAT and PKCε-CAT).…”

Section: A Constitutively Active Form Of Pkcε Mimics Pma In Its Abilimentioning

confidence: 99%

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: A Constitutively Active Form Of Pkcε Mimics Pma In Its Abilimentioning

confidence: 99%

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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“…Activation of Ets-1 occurs via Ras-mitogen activated protein kinase (MAPK) signaling involving Mek-1 and Erk-1/2 kinases. Activated Ets-1 was shown to transactivate PTHrP using an Ets-binding site in P3 in breast cancer cells, [38][39][40] murine keratinocytes 41 and HTLV-1-infected cells. 30 We have previously reported that severe combined immunodeficient (SCID)/beige (bg) mice inoculated with ATLL cells develop solid lymphoma and HHM characterized by severe hypercalcemia, increased osteoclastic bone resorption, decreased bone mineral density and increased circulating PTHrP that correlated positively with plasma calcium concentrations.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma

et al. 2005

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Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy seen in the majority of adult T-cell leukemia/lymphoma (ATLL) patients with human T-cell lymphotropic virus type-1 (HTLV-1) infection. HTLV-1 Tax has been shown to complex with ETS-1 and SP1 to transactivate the PTHrP P3 promoter. Previously, we established a SCID/bg mouse model of human ATL with RV-ATL cells and showed that PTHrP expression was independent of Tax. In this study, we report an inverse correlation of PTHrP with tax/rex mRNA in multiple HTLV-1-positive cell lines and RV-ATL cells. Stimulation of Jurkat T cells with PMA/ionomycin upregulated the PTHrP P3 promoter by a previously characterized Ets binding site and also induced protein/DNA complex formation identical to that observed in RV-ATL cells. Further, we provide evidence that cotransfection with Ets-1 and constitutively active Mek-1 in HTLV-1-negative transformed T cells with stimulation by PMA/ionomycin not only resulted in a robust induction of PTHrP P3 but also formed a complex with ETS-1/P3 EBS similar to that in ATLL cells. Our data demonstrate that transcriptional regulation of PTHrP in ATLL cells can be controlled by T-cell receptor signaling and the ETS and MAPK ERK pathway in a Tax-independent manner.

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“…Upon activation, the PKC proteins associate with the phosphatidylserines of membranes, now able to phosphorylate a variety of substrates. Like Ets1, PKCa is primarily expressed in invasive cancer cells (Platet et al, 1998;Lindemann et al, 2003). It is able to induce an aggressive neoplastic phenotype when overexpressed (Ways et al, 1995) and has been shown to contribute to tumor growth in mice (Sioud and Sorensen, 1998).…”

Section: Introductionmentioning

confidence: 99%

Ets1 is an effector of protein kinase Cα in cancer cells

Vetter¹,

Blumenthal

Lindemann

et al. 2004

Oncogene

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PKCa and Ets1 are both associated with breast cancer progression. Our previous studies suggested that these proteins are likely to functionally interact with one another. Here, we show that attenuation of endogenous PKCa expression (siPa) by RNA interference leads to reduced Ets1 protein expression in a variety of cancer cells. Pulse-chase experiments and treatment with proteasome inhibitor MG-132 revealed that siPa interferes with both Ets1 protein synthesis and stability. The effect of siPa on Ets1 expression could be partially prevented by KN-93, suggesting that calcium/calmodulin-dependent kinase II (CaMKII), a modulator of Ets1 activity, may play a role in PKCa-dependent Ets1 regulation. In contrast, Ets1-regulating kinases ERK1/ 2 were not found to be involved in this process. To assess the importance of the PKCa/Ets1 interaction, we compared the biological responses of MDA-MB-231 cells to PKCa-and Ets1-specific siRNAs (siE1). While only siPa induced changes in cellular morphology and anchorage-independent growth, both siRNAs similarly affected cellular responses to the antitumor drug mithramycin A and to UV light. Microarray analyses further showed that the expression of a certain set of genes was equally affected by siPa and siE1. The data suggest that Ets1 serves as an effector for PKCa to fulfil certain functions in cancer cells.

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Protein kinase Cα regulates Ets1 transcriptional activity in invasive breast cancer cells

Cited by 27 publications

References 0 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

Transcriptional regulation of parathyroid hormone-related protein promoter P3 by ETS-1 in adult T-cell leukemia/lymphoma

Ets1 is an effector of protein kinase Cα in cancer cells

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