A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer

Blish, Kimberly Rose; Wang, Wei; Willingham, Mark C.; Du, Wei; Birse, Charles E.; Krishnan, Surekha R.; Brown, Julie C.; Hawkins, Gregory A.; Garvin, A. Julian; D’Agostino, Ralph B.; Torti, Frank M.; Torti, Suzy V.

doi:10.1091/mbc.e07-05-0433

Cited by 58 publications

(71 citation statements)

References 47 publications

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“…The following primers were used: for hepcidin, forward, 5Ј-CTGCAACCCCAGGACAGAG-3Ј, and reverse, 5Ј-GGAATAAATAAGGAAGGGAGGGG-3Ј (37); and for ferritin H, forward, 5Ј-CTTTGACCGCGATGATGT-GGCTTT-3Ј, and reverse, 5Ј-TTTGTCAGTGGCCAGTTTG-TGCAG-3Ј. The results were normalized using GAPDH as a control, as previously described (38).…”

Section: Methodsmentioning

confidence: 99%

Post-transcriptional Modulation of Iron Homeostasis during p53-dependent Growth Arrest

Zhang

Wang

Tsuji

et al. 2008

Journal of Biological Chemistry

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Iron plays an essential role in cell proliferation and is a required cofactor for a number of critical cellular enzymes. In this report we investigate changes in proteins of iron metabolism during p53-mediated replicative arrest. Following the induction of p53 in H1299 lung cancer cells containing a doxycycline-inducible p53, an increase in both H and L subunits of ferritin protein was observed. To determine the mechanism of this effect, we investigated the ability of p53 to regulate ferritin. Real time reverse transcription-PCR demonstrated no difference in levels of ferritin H mRNA in the presence and absence of p53. Because these results suggested that transcriptional mechanisms were not responsible for the p53-dependent increase in ferritin, we tested whether a post-transcriptional mechanism was involved. RNA bandshift assays revealed that induction of p53 decreased iron regulatory protein binding. Consistent with this observation, Western blot analysis revealed a decline in transferrin receptor 1 protein levels following induction of p53. Collectively, these results suggest that p53 may induce cell cycle arrest not only by well described mechanisms involving the induction of cyclin-dependent kinase inhibitors but also by the recruitment of pathways that reduce the availability of intracellular iron.The p53 tumor suppressor protein is a critical mediator of cell cycle arrest and apoptosis. p53 is a nuclear transcription factor that is activated by cellular stress, including DNA damage, hypoxia, ribosomal stress, and loss of adhesion (reviewed in Ref. 1). Following its induction, p53 transcriptionally induces a set of genes that can promote growth arrest, cell death, or senescence, including p21 waf1 , bax, fas, and KILLER/DR5 (2). p53 can also function as a transcriptional repressor (3). Whether a cell undergoes cell cycle arrest or apoptosis in response to p53 depends on several factors, including the presence of extracellular survival factors, the presence of other oncogenic alterations, and the availability of additional transcription factors or cofactors, as well as the character and magnitude of p53 induction (4 -6). In addition to its role as a transcription factor, p53 exhibits transcription-independent functions in the cytosol that augment its pro-apoptotic activity (1). Although an increase in reactive oxygen species may contribute to p53-mediated apoptosis (7), p53 can also play a role as an antioxidant (8) by inducing genes that reduce reactive oxygen species, such as TIGAR (9), sestrins (10), and ALDH4 (11).Iron is critically important for cell growth and proliferation. Iron is required for the activity of ribonucleotide reductase, the rate-limiting enzyme for de novo DNA synthesis (12). It is also an important cofactor of the G 1 phase cyclins E/cdk2, D/cdk5 (13), D1 (14), and the S phase cyclin A/cdk2 (15), as well as numerous proteins involved in respiration and energy metabolism. Accordingly, iron deprivation inhibits proliferation. For example, small molecule iron chelators that sequester ir...

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Section: Methodsmentioning

confidence: 99%

Post-transcriptional Modulation of Iron Homeostasis during p53-dependent Growth Arrest

Zhang

Wang

Tsuji

et al. 2008

Journal of Biological Chemistry

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“…In Xenopus Wise appears to be a contextdependent regulator of Wnt signaling; it may inhibit or activate Wnt signaling in different assays (Itasaki et al 2003). In cell culture Wise blocks Wnt1 and Wnt3a activities in reporter assays (Yanagita et al 2004;Blish et al 2008). It interacts with LRP6 through one of the three loops formed by the cystine knot (Lintern et al 2009) and is able to competewith Wnt8 for binding to LRP6 (Fig.…”

Section: Wise and Sostmentioning

confidence: 99%

Secreted and Transmembrane Wnt Inhibitors and Activators

Cruciat

Niehrs

2012

Cold Spring Harbor Perspectives in Biology

537

450

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“…Because published studies have suggested the dysregulation of BMPs in RCC (11,13), tetracycline-inducible human BMP-6 expression system based on lentivirus was established in a murine RCC cell line, RenCa. Human BMP-6 cDNA was chosen to track the expression of exogenous BMP-6.…”

Section: Bmp-6 Is Protumorigenic In Rcc Cellsmentioning

confidence: 99%

“…More recently, we and others have reported that BMPs regulate the immune system as BMP-6 inhibits B-and T-cell proliferation (7,8) and activates macrophages (9,10). In the context of RCC, BMP-4, -6, and -7 are often overexpressed (11,12), whereas BMP antagonist Sclerostin domain-containing-1 (SOSTDC1) is downregulated (13). At the same time, we observed that human RCC cells frequently have a loss of expression of BMP receptors (11), suggesting a paracrine role for BMP-6 in RCC.…”

Section: Introductionmentioning

confidence: 99%

BMP-6 in Renal Cell Carcinoma Promotes Tumor Proliferation through IL-10–Dependent M2 Polarization of Tumor-Associated Macrophages

Lee

Woo

et al. 2013

Cancer Research

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Dysregulated bone morphogenetic proteins (BMP) may contribute to the development and progression of renal cell carcinoma (RCC). Herein, we report that BMP-6 promotes the growth of RCC by interleukin (IL)-10-mediated M2 polarization of tumor-associated macrophages (TAM). BMP-6-mediated IL-10 expression in macrophages required Smad5 and STAT3. In human RCC specimens, the three-marker signature BMP-6/IL-10/CD68 was associated with a poor prognosis. Furthermore, patients with elevated IL-10 serum levels had worse outcome after surgery. Together, our results suggest that BMP-6/macrophage/IL-10 regulates M2 polarization of TAMs in RCC.

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A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer

Cited by 58 publications

References 47 publications

Post-transcriptional Modulation of Iron Homeostasis during p53-dependent Growth Arrest

Post-transcriptional Modulation of Iron Homeostasis during p53-dependent Growth Arrest

Secreted and Transmembrane Wnt Inhibitors and Activators

BMP-6 in Renal Cell Carcinoma Promotes Tumor Proliferation through IL-10–Dependent M2 Polarization of Tumor-Associated Macrophages

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