A Conditional Mouse Mutant in the Tumor Suppressor SdhD Gene Unveils a Link between p21WAF1/Cip1 Induction and Mitochondrial Dysfunction

Millán-Uclés, África; Díaz-Castro, Blanca; García-Flores, Paula; Báez, Alicia; Pérez-Simón, Josè Antonio; López‐Barneo, José; Piruat, José I.

doi:10.1371/journal.pone.0085528

Cited by 17 publications

(28 citation statements)

References 44 publications

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“…64,65 This suggests that epigenetic silencing of SDH could also be an important mechanism involved in tumor development and could explain SDH deficiency in the absence of germ-line mutations. Tumorigenesis caused by haploinsufficiency seems unlikely because SDHD, SDHD/H19, and SDHB knockout mice, as well as conditional or inducible tissue-specific SDHD knockouts, do not develop tumors or any other genotype-related pathology except for a slight carotid body hyperplasia [66][67][68][69] (Judith Favier, personal communication).…”

Section: Mechanisms Of Biallelic Inactivationmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a heterotetramer protein complex consisting of four subunits encoded by nuclear genes. These include SDHA and SDHB, which form the catalytic domain, and SDHC and SDHD, which anchor the complex to the inner mitochondrial membrane. 1 The assembly factors, SDHAF1 and SDHAF2, ensure both structural and functional integrity of the complex. 2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate. 1 The TCA cycle is central to the metabolism of sugars, lipids, and amino acids and is a major source of adenosine triphosphate in cells. In addition, the cycle also seems to be involved in tumorigenesis; enzymes of the TCA cycle are involved in the pathogenesis of several tumor types. SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. 12-14 The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α. This results in activation of the hypoxia pathway, which supports tumor formation by activating angiogenesis, glucose metabolism, cell motility, and cell survival. Furthermore, defects in these enzymes lead to epigenetic alterations through an accumulation of oncometabolites inhibiting α-ketoglutarate-dependent dioxygenases, which are involved in DNA and histone demethylation. In addition to SDH-associated tumorigenesis, constitutional complex II deficiencies caused by SDHA, SDHB, SDHD, and SDHAF1 mutations may also lead to Leigh syndrome, infantile leukodystrophies, and cardiomyopathy. 3,[17][18][19] In the current review, our aim is to report all currently known SDH mutations and define their nature and spectrum in SDHrelated tumors, including PCCs/PGLs, GISTs, RCCs, and PAs, as well as in other unusual tumors arising in SDH mutation carriers. We performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor and compared the results with those of SDHA/SDHB immunohistochemistry (IHC) to predict the functional impact of nonsynonymous mutations. Finally, we explored and report here the nature of the second hit in all tumors arising in the SDH deficiency setting. The tricarboxylic acid, or Krebs, cycle is cent...

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Section: Mechanisms Of Biallelic Inactivationmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

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“…Previous efforts to study tumorigenesis in vivo did not identify an effect of mutant IDH , FH , or SDH genes, including in tissues clearly affected in human patients (Lu, et al 2013; Millan-Ucles et al 2014; Szarek et al 2015). In this report, we address the role of SDHD in thyroid cancer by ablating Sdhd in the thyroid gland.…”

Section: Discussionmentioning

confidence: 99%

“…Sdhd loxP/loxP mice (Millan-Ucles et al 2014) were crossed with Thyroid Peroxidase (TPO)–cre (Kusakabe, et al 2004) to generate Sdhd-TpoKO . In addition, Pten loxP/loxP mice (Pten-TpoKO) were generated as described previously (Pringle, et al 2012).…”

Section: Methodsmentioning

confidence: 99%

“…The spectrum of tumors caused by mutations in each of these genes differs, although there may be some overlap among the syndromes. Inherited or somatic mutations in any of the four subunits of SDH can lead to pheochromocytoma, paraganglioma, renal cell carcinoma, gastrointestinal stromal tumor, thyroid cancer and breast cancer (Bardella et al 2011; Letouze et al 2013; Millan-Ucles, et al 2014; Williamson, et al 2015; Xiao, et al 2012). …”

Section: Introductionmentioning

confidence: 99%

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Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype

Ashtekar

Huk

Magner

et al. 2017

Endocrine-Related Cancer

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Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas, and pheochromocytomas. In recent studies, missense mutations in the Succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (SDHD) in the thyroid. We report that these mice develop enlarged thyroid glands with follicle hypercellularity and increased proliferation. In vitro, human thyroid cell lines with knockdown of SDHD exhibit an enhanced migratory capability, despite no change in proliferative capacity. Interestingly, these cells acquire stem-like features which are also observed in the mouse tumors. The stem-like characteristics are reversed by α-ketoglutarate, suggesting that SDH-associated tumorigenesis results from dedifferentiation driven by an imbalance in cellular metabolites of the TCA cycle. The results of this study reveal a metabolic vulnerability for potential future treatment of SDH-associated neoplasia.

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“…Heterozygous inactivation of Sdhb or Sdhd genes in mice does not lead to tumor development, in particular while homozygous inactivation is embryonic lethal (Bayley et al 2009a,b, Piruat & Millán-Uclés 2014. Sdhd conditional constitutional or paraganglia-confined homozygous deletions also show no evidence of tumor development (Diaz-Castro et al 2012).…”

Section: Endocrine-related Cancermentioning

confidence: 99%

15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations

Baysal

Maher

2015

Endocrine-Related Cancer

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Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of a-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.

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A Conditional Mouse Mutant in the Tumor Suppressor SdhD Gene Unveils a Link between p21WAF1/Cip1 Induction and Mitochondrial Dysfunction

Cited by 17 publications

References 44 publications

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype

15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations

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