Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action
Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linke...
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MDPI AG
2022-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/10/1627 |
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| author | Rive Sarfstein Karthik Nagaraj Shivang Parikh Carmit Levy Zvi Laron Dafna Benayahu Haim Werner |
| author_facet | Rive Sarfstein Karthik Nagaraj Shivang Parikh Carmit Levy Zvi Laron Dafna Benayahu Haim Werner |
| author_sort | Rive Sarfstein |
| collection | DOAJ |
| description | Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor (<i>GHR</i>) gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 (<i>UGT2B15</i>) was the top up-regulated gene in LS. The <i>UGT2B15</i> gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of <i>UGT2B15</i> gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, <i>UGT2B15</i> expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient’s protection from genotoxic damage. |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:10:44Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-849f6f5318a646e0bf37f3ee2029a5582023-11-23T10:27:21ZengMDPI AGCells2073-44092022-05-011110162710.3390/cells11101627Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin ActionRive Sarfstein0Karthik Nagaraj1Shivang Parikh2Carmit Levy3Zvi Laron4Dafna Benayahu5Haim Werner6Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelEndocrinology and Diabetes Research Unit, Schneider Children’s Medical Center, Petah Tikva 49292, IsraelDepartment of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, IsraelNormal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor (<i>GHR</i>) gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 (<i>UGT2B15</i>) was the top up-regulated gene in LS. The <i>UGT2B15</i> gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of <i>UGT2B15</i> gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, <i>UGT2B15</i> expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient’s protection from genotoxic damage.https://www.mdpi.com/2073-4409/11/10/1627insulin-like growth factor-1 (IGF1)growth hormone receptorUGT2B15Laron syndromep53 |
| spellingShingle | Rive Sarfstein Karthik Nagaraj Shivang Parikh Carmit Levy Zvi Laron Dafna Benayahu Haim Werner Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action Cells insulin-like growth factor-1 (IGF1) growth hormone receptor UGT2B15 Laron syndrome p53 |
| title | Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action |
| title_full | Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action |
| title_fullStr | Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action |
| title_full_unstemmed | Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action |
| title_short | Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action |
| title_sort | identification of udp glucuronosyltransferase 2b15 ugt2b15 as a target for igf1 and insulin action |
| topic | insulin-like growth factor-1 (IGF1) growth hormone receptor UGT2B15 Laron syndrome p53 |
| url | https://www.mdpi.com/2073-4409/11/10/1627 |
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