Regulation of <i>Her2/neu</i> promoter activity by the ETS transcription factor, ER81

Bosc, Denis G.; Janknecht, Ralf

doi:10.1002/jcb.10205

Cited by 45 publications

(39 citation statements)

References 45 publications

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“…ER81 is associated with cellular proliferation, and in particular it was found overexpressed in several breast cancer cell lines. Moreover, it is a target of the transmembrane receptor kinase Her2/Neu (de Launoit et al, 2000;Bosc et al, 2001;Bosc and Janknecht, 2002;Goel and Janknecht, 2004) and can activate SMAD7, an inhibitor of the TGF-␤ pathway, which is often affected in several forms of cancer and cellular hyperproliferation (Dowdy et al, 2003). Therefore, the expanded expression of ER81, in conjunction with precursor cell expansion in the SVZ, seems to be particularly interesting and may highlight a function of VAX1 in the repression of ER81 and possibly a role for Vax genes in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Defective Postnatal Neurogenesis and Disorganization of the Rostral Migratory Stream in Absence of theVax1Homeobox Gene

Soria¹,

Taglialatela²,

Gil-Perotín³

et al. 2004

J. Neurosci.

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The subventricular zone (SVZ) is one of the sources of adult neural stem cells (ANSCs) in the mouse brain. Precursor cells proliferate in the SVZ and migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate into granule and periglomerular cells. Few transcription factors are known to be responsible for regulating NSC proliferation, migration, and differentiation processes; even fewer have been found to be responsible for the organization of the SVZ and RMS. For this reason, we studied the ventral anterior homeobox (Vax1) gene in NSC proliferation and in SVZ organization. We found that Vax1 is strongly expressed in the SVZ and in the RMS and that, in the absence of Vax1, embryonic precursor cells proliferate 100 times more than wild-type controls, in vitro. The SVZ of Vax1 Ϫ/Ϫ brains is hyperplastic and mostly disorganized, and the RMS is missing, causing a failure of precursor cell migration to the OBs, which as a result are severely hypoplastic. Moreover, we found that Vax1 is essential for the correct differentiation of ependyma and astrocytes.Together, these data indicate that Vax1 is a potent regulator of SVZ organization and NSC proliferation, with important consequences on postnatal neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Defective Postnatal Neurogenesis and Disorganization of the Rostral Migratory Stream in Absence of theVax1Homeobox Gene

Soria¹,

Taglialatela²,

Gil-Perotín³

et al. 2004

J. Neurosci.

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“…In addition, ER81 expression is up-regulated in mammaries of mice specifically overexpressing the HER2/Neu proto-oncogene in this organ (6,12,13), and ER81 itself enhances the transcription of the HER2/Neu gene (14). These observations suggest that the ER81 protein may be involved in breast tumor formation.…”

mentioning

confidence: 83%

Regulation of the ETS Transcription Factor ER81 by the 90-kDa Ribosomal S6 Kinase 1 and Protein Kinase A

Janknecht

2002

Journal of Biological Chemistry

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The ETS transcription factor ER81 is activated in response to many signals via mitogen-activated protein kinases (MAPKs). However, ER81 is not only phosphorylated on MAPK sites but also at other sites that impact on its transactivation potential. Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. The transcription factor ER81 belongs to the family of ETS proteins that are characterized by a conserved, ϳ85-amino acid-long, DNA-binding ETS domain and perform many essential functions in homeostasis, signaling response, and development (1-4). In addition to its ETS domain, ER81 possesses three further functional domains, an N-terminal and a C-terminal transactivation domain as well as a central inhibitory domain that regulates both transactivation domains (5). Gene transcription mediated by ER81 is strongly stimulated by mitogen-activated protein kinases (MAPKs), 1 which involves phosphorylation of ER81 at multiple sites (5, 6). Furthermore, ER81 is stimulated by the cAMP-dependent protein kinase A (PKA), although it is at present unknown whether ER81 is directly phosphorylated by PKA in vivo and how this may affect its ability to up-regulate gene transcription (7). Expression of ER81 is both developmentally and tissue-specifically regulated. For instance, high levels of ER81 expression are detectable in the adult brain, heart, or lung, whereas very little is found in liver or skeletal muscle (1,8). Moreover, ER81 expression is undetectable during early embryogenesis yet at later stages is observable at various sites in the embryo, including the central nervous system, eye, heart, lung, salivary gland, kidney, and pituitary gland (9, 10). An ER81 knock-out mouse revealed that the ER81 protein is required for the proper connection of sensory and motor neurons in the developing spinal cord, and its absence causes severe motor discoordination (11).ER81 expression has also been noted in breast tissue, and a subset of breast cancer cell lines even overexpresses ER81. In addition, ER81 expression is up-regulated in mammaries of mice specifically overexpressing the HER2/Neu proto-oncogene in this organ (6,12,13), and ER81 itself enhances the transcription of the HER2/Neu gene (14). These observations suggest that the ER81 protein may be involved in breast tumor formation. Indeed, ER81 is a downstream target of the transmembrane receptor tyrosine kinase HER2/Neu, whose overexpression in ϳ30% of human breast cancers is correlated to a poor prognosis, and ER81 may thus execute the deleterious effects of HER2/Neu in breast as well as in ovarian, gastric, and lung cancer (6,15,16). Furthermore, ER81 has been shown to up-regulate transcription of two matrix metalloproteinase genes, interstitial collagenase and matrilysin, which may contribute to the high metastatic potential of HER2/Neu-overexpressing cancer cells through an enhanced ability to ...

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“…Furthermore, ER81, or the related ETS proteins ERM and PEA3, appear to be overexpressed in HER2/Neu-overexpressing human breast cancers, and transgenic mice overexpressing HER2/Neu in mammary tissue accordingly display a coordinate up-regulation of ER81, ERM, and PEA3 (42, 45, 74). Also, both ER81 and PEA3 have been shown to activate HER2/Neu transcription, thereby establishing a positive feedback loop (53,75). Regarding all these facts, HER2/Neu and ER81, or ERM or PEA3, are destined to cooperate in up-regulating Smad7.…”

Section: Smad7 Activation By Her2/neu Tak1 and Er81mentioning

confidence: 99%

“…However, ER81 readily associated with the ETS2/3 probe containing the closely juxtaposed ETS2 and ETS3 sites, and an anti-ER81 antibody elicited a respective supershift formation. Interestingly, much more DNA binding was observable in the presence of the anti-ER81 antibody that probably stabilizes DNA binding by relieving an intramolecular repression (42,53). However, when the ETS2 site was mutated, ER81 binding was no longer observable (see ETSm2/3 in Fig.…”

Section: Her2/neu and Er81 Synergistically Activate The Smad7mentioning

confidence: 99%

HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

Dowdy¹,

Mariani²,

Janknecht

2003

Journal of Biological Chemistry

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The cytokine transforming growth factor ␤ (TGF-␤) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-␤ signaling components or enhanced expression of inhibitors of the TGF-␤ pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 upregulation. Moreover, we show that TAK1, a TGF-␤-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-␤ signaling by activating Smad7 transcription may proceed not only through TGF-␤ receptorregulated Smad proteins but also through an independent pathway involving ER81 and TAK1.

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Regulation of Her2/neu promoter activity by the ETS transcription factor, ER81

Cited by 45 publications

References 45 publications

Defective Postnatal Neurogenesis and Disorganization of the Rostral Migratory Stream in Absence of theVax1Homeobox Gene

Defective Postnatal Neurogenesis and Disorganization of the Rostral Migratory Stream in Absence of theVax1Homeobox Gene

Regulation of the ETS Transcription Factor ER81 by the 90-kDa Ribosomal S6 Kinase 1 and Protein Kinase A

HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

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