A conditional mouse mutant in the tumor suppressor SdhD gene unveils a link between p21(WAF1/Cip1) induction and
Africa Millán-Uclés1, Blanca Díaz-Castro2, Paula García-Flores2
1Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla. Seville, Spain ; Departamento de Hematología. Hospital Universitario Virgen del Rocío. Seville, Spain.
Abstract:
Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/paraganglioma tumors. Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of the hypoxia-inducible factor 1α (Hif1α) at normal oxygen tension, a theory referred to as "pseudo-hypoxic drive". Other molecular processes, such as oxidative stress, apoptosis, or chromatin remodeling have been also proposed to play a causative role. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. Moreover, the biological factors that determine the tissue-specificity of these tumors have not been identified. In this work, we made use of the inducible SDHD-ESR mouse, a conditional mutant in the SdhD gene, which encodes the small subunit of MCII, and that acts as a tumor suppressor gene in humans. The analysis of the Hif1α pathway in SDHD-ESR tissues and in two newly derived cell lines after complete SdhD loss -a requirement for hereditary paraganglioma type-1 tumor formation in humans- partially recapitulated the "pseudo-hypoxic" response and rendered inconsistent results. Therefore, we performed microarray analysis of adrenal medulla and kidney in order to identify other early gene expression changes elicited by SdhD deletion. Our results revealed that each mutant tissue displayed different variations in their gene expression profiles affecting to different biological processes. However, we found that the Cdkn1a gene was up-regulated in both tissues. This gene encodes the cyclin-dependent kinase inhibitor p21(WAF1/Cip1), a factor implicated in cell cycle, senescence, and cancer. The two SDHD-ESR cell lines also showed accumulation of this protein. This new and unprecedented evidence for a link between SdhD dysfunction and p21(WAF1/Cip1) will open new avenues for the study of the mechanisms that cause tumors in Sdh mutants. Finally, we discuss the actual role of Hif1α in tumorigenesis.
Insights
Mitochondrial complex II gene mutations cause tumors. This study found that SdhD gene loss up-regulates the CDKN1A gene, encoding p21(WAF1/Cip1), linking SdhD dysfunction to tumor development.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Mutations in mitochondrial complex II (MCII) genes, specifically succinate dehydrogenase (Sdh), are linked to familiar pheochromocytoma/paraganglioma tumors.
- The
- pseudo-hypoxic drive
- theory, involving constitutive hypoxia-inducible factor 1α (Hif1α) expression, is the leading explanation for Sdh-mutation-induced tumorigenesis, though other factors like oxidative stress and apoptosis are also implicated.
- The precise mechanisms and tissue-specific factors driving Sdh-mutation tumorigenesis remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying SdhD gene mutation-induced tumorigenesis.
- To identify early gene expression changes in response to SdhD loss.
- To explore the role of p21(WAF1/Cip1) in Sdh-mutant tumors.
Main Methods:
- Utilized an inducible SDHD-ESR mouse model with conditional SdhD gene mutation.
- Analyzed Hif1α pathway activity in mutant tissues and derived cell lines.
- Performed microarray analysis on adrenal medulla and kidney tissues after SdhD deletion.
- Assessed p21(WAF1/Cip1) protein levels in cell lines.
Main Results:
- The Hif1α pathway analysis showed inconsistent results, partially recapitulating the "pseudo-hypoxic" response.
- Microarray analysis revealed distinct gene expression profile variations in adrenal medulla and kidney tissues.
- The CDKN1A gene, encoding p21(WAF1/Cip1), was significantly up-regulated in both mutant tissues.
- p21(WAF1/Cip1) protein accumulation was observed in SDHD-ESR cell lines.
Conclusions:
- SdhD gene dysfunction is linked to the up-regulation of CDKN1A and p21(WAF1/Cip1).
- This finding provides new insights into the mechanisms of Sdh-mutant tumorigenesis.
- Further research is warranted to elucidate the exact role of Hif1α and p21(WAF1/Cip1) in these tumors.
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