The EGF/TGFα response element within the TGFα promoter consists of a multi-complex regulatory element

Awwad, Rana A.; Humphrey, Lisa E.; Periyasamy, Baskar; Scovell, William M.; Li, Wenhui; Coleman, Kevin; Lynch, Mark; Carboni, Joan; Brattain, Michael G.; Howell, Gillian

doi:10.1038/sj.onc.1202982

Cited by 9 publications

(4 citation statements)

References 56 publications

(56 reference statements)

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“…In fact, primary cultures of hyperplasic human parathyroid cells increase rather than suppress growth with elevations in calcium concentration in the incubation media (21). In tumors in which growth is driven by TGF-␣ EGFR overexpression, TGF-␣ activation of the EGFR also results in further stimulation of TGF-␣ gene transcription (3,7), thus generating a positive feedback loop that furthers cell growth. Anti-EGFR therapy allowed us to examine whether TGF-␣ activation of the EGFR was involved in the control of TGF-␣ expression in the parathyroid glands.…”

Section: Discussionmentioning

confidence: 99%

A critical role for enhanced TGF-α and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease

Cozzolino¹,

Lü²,

Sato³

et al. 2005

American Journal of Physiology-Renal Physiology

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The parathyroid hyperplasia secondary to kidney disease is associated with enhanced expression of the growth promoter transforming growth factor-alpha (TGF-alpha). TGF-alpha stimulates growth through activation of its receptor, the epidermal growth factor receptor (EGFR), normally expressed in the parathyroid glands. Because enhanced coexpression of TGF-alpha and EGFR causes aggressive cellular growth, these studies utilized highly specific inhibitors of EGFR tyrosine kinase, a step mandatory for TGF-alpha-induced EGFR activation, to assess the contribution of growth signals from enhanced expression of TGF-alpha exclusively or both TGF-alpha and EGFR to the rapid parathyroid growth induced by kidney disease and exacerbated by high-phosphorus (P) and low-calcium (Ca) diets in rats. The enhancement in parathyroid gland weight and proliferating activity (proliferating cell nuclear antigen/Ki67) induced by kidney disease and aggravated by either high P or low Ca intake, within the first week after 5/6 nephrectomy, in rats, coincided with simultaneous increases (2- to 3-fold) in TGF-alpha and EGFR content. Conversely, prevention of the increases in both TGF-alpha and EGFR paralleled the efficacy of either P restriction or high-Ca intake in ameliorating uremia-induced parathyroid hyperplasia. More importantly, suppression of TGF-alpha/EGFR signaling, through prophylactic administration of potent and highly selective inhibitors of ligand-induced EGFR activation, completely prevented both high-P- and low-Ca-induced parathyroid hyperplasia as well as TGF-alpha self-upregulation. Thus enhanced parathyroid TGF-alpha/EGFR expression, self-upregulation, and growth signals occur early in kidney disease, are aggravated by low-Ca and high-P intake, and constitute the main pathogenic mechanism of the severity of parathyroid hyperplasia.

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Section: Discussionmentioning

confidence: 99%

A critical role for enhanced TGF-α and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease

Cozzolino¹,

Lü²,

Sato³

et al. 2005

American Journal of Physiology-Renal Physiology

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“…TPA up-regulates TGF-␣ expression through signaling via protein kinase C (PKC)-dependent and -independent pathways (57). In the latter case, it is well-documented that TGF-␣ is an autoinductive cytokine and that the TGF-␣ gene promoter contains a TGF-␣/epidermal growth factor-responsive element (58). It has also been shown that TGF-␤1 transcriptionally regulates TGF-␣ expression (59).…”

Section: Discussionmentioning

confidence: 99%

Smad3 Knockout Mice Exhibit a Resistance to Skin Chemical Carcinogenesis

Zhang

et al. 2004

Cancer Research

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ABSTRACT؉/؉ mice, suggesting a Smad3 gene dosage effect. Given that TGF-␤1 is a well-documented TPA-responsive gene and also has a potent chemotactic effect on macrophages, our study suggests that Smad3 may be required for TPA-mediated tumor promotion through inducing TGF-␤1-responsive genes, which are required for tumor promotion, and through mediating TGF-␤1-induced macrophage infiltration.

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“…Binding of EGFR to its cognate ligands leads to autophosphorylation of RTK and subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival [Yarden and Sliwkowski, 2001]. Moreover, it is reported that the ligands of EGFR generally act over short distances as autocrine or paracrine to stimulate EGFR expression and signal amplification [Tsao et al, 1996; Rusch et al, 1997; Piepkorn et al, 1998; Awwad et al, 1999; Arteaga, 2002]. The mRNA subtraction analysis of eGFP/A431 and ECPsp‐eGFP/A431 cells showed that the EGFR was upregulated at the mRNA levels (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Signal peptide of eosinophil cationic protein upregulates transforming growth factor‐alpha expression in human cells

Chang

Kao

et al. 2006

J of Cellular Biochemistry

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Eosinophil cationic protein (ECP) is a major component of eosinophil granule protein that is used as a clinical bio-marker for asthma and allergic inflammatory diseases. Previously, it has been reported that the signal peptide of human ECP (ECPsp) inhibits the cell growth of Escherichia coli (E. coli) and Pichia pastoris (P. pastoris), but not mammalian A431 cells. The inhibitory effect is due to the lack of human signal peptide peptidase (hSPP), a protease located on the endoplasmic reticulum (ER) membrane, in the lower organisms. In this study, we show that the epidermal growth factor receptor (EGFR) is upregulated by the exogenous ECPsp-eGFP as a result of the increased expression of the transforming growth factor-alpha (TGF-alpha) at both transcriptional and translational levels in A431 and HL-60 clone 15 cell lines. Furthermore, the N-terminus of ECPsp fragment generated by the cleavage of hSPP (ECPspM1-G17) gives rise to over threefold increase of TGF-alpha protein expression, whereas another ECPsp fragment (ECPspL18-A27) and the hSPP-resistant ECPsp (ECPspG17L) do not show similar effect. Our results indicate that the ECPspM1-G17 plays a crucial role in the upregulation of TGF-alpha, suggesting that the ECPsp not only directs the secretion of mature ECP, but also involves in the autocrine system.

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The EGF/TGFα response element within the TGFα promoter consists of a multi-complex regulatory element

Cited by 9 publications

References 56 publications

A critical role for enhanced TGF-α and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease

A critical role for enhanced TGF-α and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease

Smad3 Knockout Mice Exhibit a Resistance to Skin Chemical Carcinogenesis

Signal peptide of eosinophil cationic protein upregulates transforming growth factor‐alpha expression in human cells

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