The role(s) of hypoxia-inducible factors (HIFs) in the development of renal cysts in mice deficient in fumarate hydratase (Fh1)
Fumarate hydratase (FH) encodes a Krebs cycle (also called TCA cycle) enzyme which converts fumarate to malate and also functions as a tumour suppressor gene. Germline mutations in FH predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Affected individuals develop benign smooth mu...
| Tác giả chính: | |
|---|---|
| Tác giả khác: | |
| Định dạng: | Luận văn |
| Ngôn ngữ: | English |
| Được phát hành: |
2011
|
| Những chủ đề: |
| Tóm tắt: | Fumarate hydratase (FH) encodes a Krebs cycle (also called TCA cycle) enzyme which converts fumarate to malate and also functions as a tumour suppressor gene. Germline mutations in FH predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Affected individuals develop benign smooth muscle tumours (leiomyomas) of the skin and uterus and renal cysts and cancers; specifically type II papillary and collecting duct carcinomas. Kidney-specific deletion of Fh1 (the murine orthologue of FH) recapitulates HLRCC in part and mice develop renal cysts that are proliferative and express constitutively hypoxia inducible factors -1α and -2α (Hif-1α and Hif-2α). This phenomenon of pseudo-hypoxia (HIF expression in normal oxygen tension) is also evident in cultured cells deficient in FH and is proposed as a possible mechanism for initiation and/or progression of carcinogenesis. We have utilised our mouse model to investigate the role of Hif-1α and Hif-2α and Fh1 in renal cyst development and show remarkably that combined genetic inactivation of Hif-1α and Fh1 increased both cyst size and frequency. However, kidneys deficient for both Fh1 and Hif-2α were comparable to those deficient for Fh1. Immunohistochemical analyses show that Fh1 inactivation leads to increased proliferation, DNA damage and affects the cell cycle in the renal cysts. Hif-1α and Hif-2α inactivation is not shown to contribute to these. Through genome-wide mRNA expression analysis we have identified that Ccnd1 is significantly upregulated (or the most significantly upregulated gene) in Fh1/Hif-1α knockout kidneys compared to wild type and Fh1 knockout kidneys. Other upregulated genes in the double knockout kidneys include genes involved in cell cycle, proliferation and structural organization of the cell. |
|---|