Stanniocalcin-1 in cell stress and differentiation

Stanniocalcin-1 (STC-1) is a 56 kD homodimeric protein which was originally identified in bony fish, where it regulates calcium/phosphate homeostasis and protects against toxic hypercalcemia. STC-1 was considered unique to fish until the cloning of cDNA for human STC-1 in 1995 and mouse Stc-1 in 1996. STC-1 is conserved through evolution with human and salmon STC-1 sharing 60% identity and 80% similarity. The surprisingly high homology between mammalian and fish STC-1 and the protective actions of STC-1 in terminally differentiated neurons, originally reported by my colleagues, prompted me to further study the role of STC-1 in cell stress and differentiation. One purpose was to determine whether there is an inter-relationship between terminally differentiated cells and STC-1 expression. The study revealed an accumulation of STC-1 in mature megakaryocytes and adipocytes, i.e. postmitotic cells with limited or lost proliferative capacity. Still proliferating uninduced cells were negative for STC-1 mRNA and protein, whereas differentiating cells accumulated STC-1 in their cytoplasm. Interestingly, in liposarcomas the grade inversely correlated with STC-1 expression. Another aim was to study how STC-1 gene expression is regulated. Given that IL-6 is a cytokine with neuroprotective actions, by unknown mechanisms, we examined whether IL-6 regulates STC-1 gene expression. Treatment of human neural Paju cells with IL-6 induced a dose-dependent upregulation of STC-1 mRNA levels. This induction of STC-1 expression by IL-6 occurred mainly through the MAPK signaling pathway. Furthermore, I studied the role of IL-6-mediated STC-1 expression as a mechanism of cytoprotection conferred by hypoxic preconditioning (HOPC) in brain and heart. My findings show that Stc-1 was upregulated in brain after hypoxia treatment. In the brain of IL-6 deficient mice, however, no upregulation of Stc-1 expression was evident. After induced brain injury the STC-1 response in brains of IL-6 transgenic mice, with IL-6 overexpression in astroglial cells, was stronger than in brains of WT mice. These results indicate that IL-6-mediated expression of STC-1 is one molecular mechanism of HOPC-induced tolerance to brain ischemia. The protection conferred by HOPC in heart occurs during a bimodal time course comprising early and delayed preconditioning. Interestingly, my results showed that the expression of Stc-1 in heart was upregulated in a biphasic manner during HOPC. IL-6 deficient mice did not, however, show a similar biphasic manner of Stc-1 upregulation as did WT mice. Instead, only an early upregulation of Stc-1 expression was evident. The results suggest that the upregulation of Stc-1 during the delayed preconditioning is IL-6-dependent. The upregulated expression of Stc-1 during the early preconditioning, however, is only partly IL-6-dependent and possibly also directly mediated by HIF-1. These findings suggest that STC-1 is a pro-survival protein for terminally differentiated cells and that STC-1 expression may in fact be regulated by stress. In addition, I show that STC-1 gene upregulation, mediated in part by IL-6, is a new mechanism of protection conferred by HOPC in brain and heart. Because of its importance for fundamental biological processes, such as differentiation and cytoprotection, STC-1 may have therapeutic implications for management of stroke, neurodegenerative diseases, cancer, and obesity.

Stanniocalcin 1 (STC-1) är ett homodimert glykoprotein som ansågs vara unikt för fiskar tills musens och människans STC-1 klonades 1995 respektive 1996. STC-1 är evolutivt tämligen oförändrat; homologin mellan fiskens och människans STC-1 är 80%. Hos fisken skyddar STC-1 mot toxiska kalciumhalter (hyperkalcemi). Funktionen hos STC-1 i däggdjur är emellertid okänd. Vår forskargrupp har tidigare påvisat att terminalt utmognade neuroner producerar STC-1 och att detta protein skyddar mot cellskada förosakad av hjärninfarkt. Mot bakgrund av dessa resultat har målsättningen med min avhandling varit att undersöka betydelsen av STC-1 vid cell stress och differentiering. Jag har funnit ett samband mellan STC-1 och terminal differentiering. Jag har visat att megakaryocyter och fettceller, båda postmitotiska, terminalt utmognade celler, producerar STC-1. Dessutom har jag påvisat, att på konstgjord väg framkallad terminal differentiering i två cellinjer, K562 och 3T3-L1, inducerar produktionen av STC-1. Jag har också påvisat att STC-1 induceras av interleukin 6 (IL-6), ett cytokin med neuroprotektiva egenskaper. Genom att utsätta vävnader för korta perioder av syrebrist (hypoxi), utvecklas ett skydd mot påföljande ischemisk skada (infarkt). Mekanismen bakom detta fenomen, även kallat hypoxic preconditioning (HOPC), är okänd. Jag har studerat HOPC - fenomenet hos möss och av mina resultat framgår det att IL-6 inducerat STC-1 är en bakomliggande mekanism till HOPC-skyddet i både hjärna och hjärta. Dessa resultat tyder på att STC-1 är en överlevnadsfaktor för terminalt utmognade celler. Stress, såsom hypoxi, utlöser sannolikt STC-1 som den skyddande faktorn. Eftersom STC-1 är involverat i så grundläggande biologiska processer som terminal differentiering och cellskydd, är dess tillämpningsområde brett och kan tänkas omfatta vården av stroke, neurodegenerativa sjukdomar, fetma och cancer.