OSGIN1

Official Full Name

oxidative stress induced growth inhibitor 1

Organism

Homo sapiens

GeneID

29948

Background

This gene encodes an oxidative stress response protein that regulates cell death. Expression of the gene is regulated by p53 and is induced by DNA damage. The protein regulates apoptosis by inducing cytochrome c release from mitochondria. It also appears to be a key regulator of both inflammatory and anti-inflammatory molecules. The loss of this protein correlates with uncontrolled cell growth and tumor formation. Naturally occurring read-through transcription exists between this gene and the neighboring upstream malonyl-CoA decarboxylase (MLYCD) gene, but the read-through transcripts are unlikely to produce a protein product. [provided by RefSeq, Aug 2011]

Synonyms

BDGI; OKL38;

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Detailed Information

Characterization of the OSGIN1 gene

Oxidative stress induced growth inhibitor 1 (OSGIN1), also named bone marrow stromal cell (BMSC)-derived growth inhibitor 1 (BDG1) or ovary, kidney and liver protein 38 (OKL38), was first identified in 2001 as a novel induced pregnancy complementary DNA (cDNA) from a human ovary cDNA library. Huynh et al. originally named the gene OKL38 based on the predominant expression of its protein product in ovary, kidney and liver and its predicted size of about 38 kDa. Nevertheless, additional aliases arose from identification of different isoforms of this gene that resulted in the discovery of a 52 kDa and a 61 kDa protein product from the same gene.

OSGIN1 balances cell growth, differentiation and death

OSGIN1 was originally identified as a novel pregnancy gene. Studies by Huynh et al. localized OSGIN1 to rat breast epithelial cells and found that it was induced during pregnancy and lactation. Further analysis of OSGIN1 in human breast cancer cell lines found that expression of the protein was abnormally low in these cells. Interestingly, the researchers found that OSGIN1 overexpression reduced tumor formation in these mice, indicating that this protein could play an important role in the differentiation and growth of cells. Further studies by Ong et al. found that overexpression of the 52 kDa OSGIN1 isoform protein may also inhibit cell proliferation, induce cell death and reduce the migration of various cancer cell lines.

Further investigation into the specific pathways associated with OSGIN1 mediated cell cycle regulation found that OSGIN1 specifically induces cell cycle arrest in the S phase resulting in the induction of apoptosis in breast cancer cells. Yao et al. expanded upon these findings in experiments involving DNA damage and confirmed that OSGIN1 regulates apoptosis through mitochondrial localization and cytochrome C release that involves the transcriptional control of tumor suppressor protein (p53) and peptidyl arginine deiminase 4 (PADI4) (Figure 1). In these studies, p53 and OSGIN1 levels were found to be repressed before DNA damage which correlated with high PADI4 expression at the OSGIN1 promoter. In contrast, increased DNA damage leads to increased p53 at the OSGIN1 promoter, increased OSGIN1 expression and suppression of PADI4. Together, PADI4 and p53 could alternately regulate the expression of OSGIN1 to mediate apoptosis during periods of cell damage (Figure 1).

Figure 1. Regulation of OSGIN1.

OSGIN1 and disease

A large number of data supporting OSGIN1 as a regulator of cell cycle stems from studies investigating tumorigenesis. Some of the first investigations of OSGIN1 found OSGIN1 to be down-regulated in 70% of kidney tumors using cancer gene profiling arrays. These findings were also paralleled in hepatocellular carcinoma (HCC) where the loss of OSGIN1 correlated with advanced tumor stages of HCC.

Many studies investigating the importance of OSGIN1 in tumorigenesis have been conducted using breast cancer cell lines. As previously mentioned, OSGIN1 was originally identified as an important gene regulated during pregnancy and is believed to contribute to mammary gland cell growth and death needed during stages of lactation. This role suggests that fluctuations in the OSGIN1 gene may be required for the cellular changes that transition a cell from a normal to a malignant state. The fluctuations of OSGIN1 in breast cells contrasts with the more stable expression of this gene in other tissue types, suggesting dysregulation of OSGIN1 in this tissue type may be causative of disease. Global gene expression profiling conducted on cancer cells treated with Taheebo identified cell growth arrest and initiation of apoptosis in these cells to be correlated with increased OSGIN1 expression. These studies suggest OSGIN1 as a tumor suppressor and thus a potential therapeutic target in cancer.

Less investigation has been conducted on the role of OSGIN1 in non-carcinogenic diseases; nevertheless, some studies target OSGIN1 as regulated during models of cardiovascular disease. Exposure to ultrafine particles (UFP), associated with ambient air pollution, has been shown to be associated with cardiovascular disease. Microarray studies showed OSGIN1 to be upregulated upon exposure to diesel exhaust particles which can adversely affect health. These findings were confirmed in a study by Li et al in 2010 that showed that UFP induced superoxide and resulted in increased OSGIN1 expression in human aortic endothelial cells (HAEC). Further research is necessary to understand the role of OSGIN1 in cardiovascular disease as well as other unstudied diseases.

References:

Tsai C H, et al. Docosahexaenoic acid increases the expression of oxidative stress-induced growth inhibitor 1 through the PI3K/Akt/Nrf2 signaling pathway in breast cancer cells. Food & Chemical Toxicology An International Journal Published for the British Industrial Biological Research Association, 2017, 108(Pt A):276.
Brennan M S, et al. The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes. Sci Rep, 2017, 7:42054.
Brennan M S. The Nrf2 transcriptional target, OSGIN1, contributes to the cytoprotective properties of dimethyl fumarate. Dissertations & Theses - Gradworks, 2014.
Jing H, et al. Interaction of OKL38 and p53 in Regulating Mitochondrial Structure and Function. Plos One, 2012, 7(8):e43362.
Liu, M., et al. Allele-specific imbalance of oxidative stress-induced growth inhibitor 1 associates with progression of hepatocellular carcinoma. Gastroenterology. 2014, 146, 1084-1096.
Li R, et al. Ultrafine particles from diesel vehicle emissions at different driving cycles induce differential vascular pro-inflammatory responses: implication of chemical components and NF-kappaB signaling. Particle & Fibre Toxicology, 2010, 7(1):6-6.

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