Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma

Macià, Anna; Gallel, Pilar; Vaquero, Marta; Gou-Fàbregas, Myriam; Santacana, Maria; Maliszewska, Agnieszka; Robledo, Mercedes; Gardiner, Jennifer R.; Basson, M. Albert; Matías‐Guiu, Xavier; Encinas, Mario

doi:10.1038/onc.2011.556

Cited by 32 publications

(35 citation statements)

References 52 publications

(63 reference statements)

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“…On the other hand, circulating T3 and T4 levels were virtually identical between genotypes, indicating that thyroids from Spry1 knockout mice are euthyroid (Figures 2c and d). These data, together with high Spry1 levels found in mouse thyroid with respect to other organs, 8 suggested that Spry1 directly influences the proliferation of follicular cells in a cell-autonomous manner. To further support this notion, we isolated follicles from 3-month-old mice of both genotypes and found that follicular cells from mutant mice proliferated faster in vitro, as measured by 5 0 -bromo-deoxyuridine uptake (Figure 2f).…”

Section: Resultsmentioning

confidence: 82%

“…We have previously shown that Spry1 knockout mice exhibit thyroid C-cell hyperplasia. 8 While examining the number of C-cells, we noticed that thyroids from 3 months old Spry1 knockout mice, although having normal shape and showing no external signs of malignant growth, were bigger than those from wild-type littermates (Figure 1a). To confirm these observations, we estimated the thyroid lobe size from 3 months old wild-type and Spry1 null littermates.…”

Section: Resultsmentioning

confidence: 99%

“…[16][17][18][19] On the other hand, our previous results show that the overexpression of Spry1 in a medullary thyroid carcinoma cell line induces cellular senescence. 8 To explore the possibility that Spry1 induces cellular senescence in follicular cells via induction of an SASP, we collected supernatants from isolated follicles from wild-type and knockout thyroids and measured 62 different cytokines and chemokines using an antibody array ( Figure 4a). Levels of IL-6, KC (CXCL1), MIPs, RANTES or sTNFRII, which are prominent SASP factors, 15 were severely reduced in supernatants from knockout cells, whereas IL-1a was not.…”

Section: Resultsmentioning

confidence: 99%

“…60 For BrdU uptake experiments, follicles were isolated as above and cultured in complete medium for 48 h. Cells were pulsed with BrdU for the last 4 h, fixed and BrdU staining performed as described. 8 Real time RT-PCR. Total RNA was extracted with a RNeasy Mini Kit (QIAGEN, Hilden, Germany).…”

Section: Spry1 and Sasp A Macià Et Almentioning

confidence: 99%

“…SA-b-Gal staining of was carried out as described. 8 Briefly, paraformaldehyde-fixed frozen sections were incubated with X-gal solution (20 mg/ml X-Gal (Sigma), 5 mM K 3 Fe(CN) 6 , 5 mM K 4 Fe(CN) 6 and 2 mM MgCl 2 ) in PBS at pH 6.0 during at least 2 h at 37 1C. To allow comparison between specimens, all samples were assayed simultaneously.…”

Section: Spry1 and Sasp A Macià Et Almentioning

confidence: 99%

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Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

et al. 2013

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Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFjB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated b-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation. The Sprouty family of genes is composed of four members in mammals (Spry1-4), orthologous to a single Drosophila melanogaster gene (dSpry). With some well-documented exceptions, Sprouty proteins function as feedback inhibitors of receptor tyrosine kinase (RTK) signaling. In Drosophila, dSpry inhibits signaling by FGF and EGF in the airways and the eye, respectively. Genetic experiments in mice establish that Spry1 and Spry2 are negative regulators of signaling by FGFR and Ret RTKs. Thus, the deletion of Spry2 and/or Spry4 causes different craniofacial abnormalities because of hypersensitivity to FGF. On the other hand, excessive Ret signaling underlies kidney and enteric nervous system defects found in Spry1 and Spry2 knockout mice, respectively (reviewed in Guy et al. 1 ). Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood. 1,2 Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies. Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.In this work, we show that Spry1 null mice exhibit overgrowth of the thyroid gland owing to increased proliferation of thyrocytes. Surprisingly, such increase in cell proliferation does not correlate with eith...

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Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Spry1 and Sasp A Macià Et Almentioning

confidence: 99%

Section: Spry1 and Sasp A Macià Et Almentioning

confidence: 99%

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Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

et al. 2013

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Cellular and molecular events on the development of mammalian thyroid C cells

Kameda

2016

Developmental Dynamics

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Thyroid C cells synthesize and secrete calcitonin, a serum calcium-lowering hormone. This review provides our current understanding of mammalian thyroid C cells from the molecular and morphological perspectives. Several transcription factors and signaling molecules involved in the development of C cells have been identified, and genes expressed in the pharyngeal pouch endoderm, neural crest-derived mesenchyme in the pharyngeal arches, and ultimobranchial body play critical roles for the development of C cells. It has been generally accepted, without much-supporting evidence, that mammalian C cells, as well as the avian cells, are derived from the neural crest. However, by fate mapping of neural crest cells in both Wnt1-Cre/ R26R and Connexin(Cxn)43-lacZ transgenic mice, we showed that neural crest cells colonize neither the fourth pharyngeal pouch nor the ultimobranchial body. E-cadherin, an epithelial cell marker, is expressed in thyroid C cells and their precursors, the fourth pharyngeal pouch and ultimobranchial body. Furthermore, E-cadherin is colocalized with calcitonin in C cells. Recently, lineage tracing in Sox17-2A-iCre/R26R mice has clarified that the pharyngeal endoderm-derived cells give rise to C cells. Together, these findings indicate that mouse thyroid C cells are endodermal in origin. Developmental Dynamics 245:323-341, 2016. V C 2015 Wiley Periodicals, Inc.

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The developing story of Sprouty and cancer

Masoumi-Moghaddam

Amini

Morris

2014

Cancer Metastasis Rev

140

181

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Sprouty proteins are evolutionarily conserved modulators of MAPK/ERK pathway. Through interacting with an increasing number of effectors, mediators, and regulators with ultimate influence on multiple targets within or beyond ERK, Sprouty orchestrates a complex, multilayered regulatory system and mediates a crosstalk among different signaling pathways for a coordinated cellular response. As such, Sprouty has been implicated in various developmental and physiological processes. Evidence shows that ERK is aberrantly activated in malignant conditions. Accordingly, Sprouty deregulation has been reported in different cancer types and shown to impact cancer development, progression, and metastasis. In this article, we have tried to provide an overview of the current knowledge about the Sprouty physiology and its regulatory functions in health, as well as an updated review of the Sprouty status in cancer. Putative implications of Sprouty in cancer biology, their clinical relevance, and their proposed applications are also revisited. As a developing story, however, role of Sprouty in cancer remains to be further elucidated.

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Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma

Cited by 32 publications

References 52 publications

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

Cellular and molecular events on the development of mammalian thyroid C cells

The developing story of Sprouty and cancer

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