Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for
A Macià1, M Vaquero1, M Gou-Fàbregas1
1Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Edifici Biomedicina I, Lab 2.8, Lleida 25198, Spain.
Abstract:
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 NFκB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated β-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.
Insights
Sprouty1 (Spry1) inhibits cell proliferation by inducing senescence through the NFκB pathway, independent of ERK signaling. Loss of Spry1 accelerates tumor formation and reduces senescence markers, highlighting its tumor-suppressive role.
Area of Science:
- Cellular biology
- Molecular oncology
- Signal transduction
Background:
- Sprouty genes (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling, proposed as tumor suppressors.
- Their precise mechanisms of inhibiting RTK signaling, particularly Spry1's role beyond the ERK pathway, remain unclear.
Purpose of the Study:
- To elucidate a novel mechanism by which Spry1 restricts cell proliferation independently of the ERK pathway.
- To investigate Spry1's role in cellular senescence and its implications in thyroid tumorigenesis.
Main Methods:
- In vivo analysis of Spry1 knockout mouse thyroid glands.
- Assessment of senescence markers (Ki67, β-galactosidase) and NFκB pathway activation.
- Comparison of Spry1 levels in human thyroid malignancies versus non-tumoral tissue.
- Evaluation of accelerated tumor formation in the context of Pten-induced tumorigenesis.
Main Results:
- Spry1 induces a senescence-associated secretory phenotype via NFκB pathway activation.
- Spry1 knockout mice exhibit larger thyroids with decreased senescence markers.
- Spry1 deficiency accelerates Pten-induced thyroid tumor formation.
- SPRY1 levels are reduced in human thyroid cancers compared to normal tissue.
Conclusions:
- Spry1 acts as a novel tumor suppressor by inducing cellular senescence through the NFκB pathway, independent of ERK signaling.
- Spry1 functions as a critical sensor of mitogenic activity, preventing uncontrolled proliferation.
- Loss of Spry1 contributes to thyroid tumorigenesis, underscoring its importance in cancer prevention.
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