Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.
Function Secreted frizzled-related protein 1 (SFRP1) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. SFRP1 and SFRP5 may be involved in determining the polarity of photoreceptor cells in the retina. SFRP1 is expressed in several human tissues, with the highest levels in the heart. The Secreted frizzled-related protein (SFRP) family consists of five secreted glycoproteins in humans (SFRP1, SFRP2, SFRP3, SFRP4, SFRP5) that act as extracellular signaling ligands. Each SFRP is ~300 amino acids in length and contains a cysteine-rich domain (CRD) that shares 30–50% sequence homology with the CRD of Frizzled (Fz) receptors. SFRPs are able to bind Wnt proteins and Fz receptors in the extracellular compartment. The interaction between SFRPs and Wnt proteins prevents the latter from binding the Fz receptors. SFRPs are also able to downregulate Wnt signaling by the formation of an inhibitory complex with the Frizzled receptors. The Wnt pathway plays a key role in embryonic development, cell differentiation and cell proliferation. It has been shown that the deregulation of this critical developmental pathway occurs in several human tumor entities. SFRP1 is a 35 kDa prototypical member of the SFRP family. It acts as a biphasic modulator of Wnt signaling, counteracting Wnt-induced effects at high concentrations and promoting them at lower concentrations. It is located in a chromosomal region (8p12-p11.1) that is frequently deleted in breast cancer and is thought to harbour a tumor suppressor gene.
Tumor suppression There are 3 types of tumor suppressor genes:
Genes that affect cell growth Genes that limit the cell cycle and induce apoptosis Genes that repair damaged DNA SFRP1 appears to fall in the first category of genes, those that affect cell growth. The role of SFRP1 as a tumor suppressor has been proposed in many cancers, based on its loss in patient tumors. Its frequent inactivation by methylation-induced silencing is consistent with it behaving as a tumor suppressor. Also, the SFRP1 gene is located in a region on chromosome 8 that is frequently lost in many cancer types. Expression levels of several targets of the Wnt signaling pathways are increased in tumor tissue compared with normal, and the expression of SFRP1 is lost in patient tumor samples. The role for the Wnt/β-catenin signaling in cancer has been well defined: β-catenin drives transcription of genes that contribute to the tumor phenotype by regulating processes such as proliferation, survival and invasion. Gumz et al. showed that SFRP1 expression in UMRC3 cells (clear cell renal cell carcinoma cell line) resulted in a growth-inhibited phenotype. SFRP1 expression not only reduced the expression of Wnt target genes, but also markedly inhibited tumor cell growth in culture, soft agar and xenografts in athymic nude mice. Growth in culture and anchorage-independent growth were inhibited in SFRP1-expressing UMRC3 cells. The growth-inhibitory effects of SFRP1 were due primarily to decreased cell proliferation rather than an increase in apoptosis. This was consistent with the effect of SFRP1 on cellular proliferation as seen in prostate cancer, where retroviral-mediated expression of SFRP1 resulted in inhibited cellular proliferation but had no effect on apoptosis. Also, restoration of SFRP1 expression attenuated the malignant phenotype of cRCC; moreover, other studies showed reexpression of SFRP1 resulted in decreased colony formation in colon and lung cancer models.
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