title: Fumarate hydratase inactivation in renal tumors: HIF1α, NRF2, and "cryptic targets" of transcription factors.
abstract: Biallelic inactivation of fumarate hydratase(FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer(HLRCC).  The most direct effect of FH inactivation is intracellular fumarate accumulation.  A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α(HIF1A) through competitive inhibition of HIF prolyl hydroxylases.  Recently, a competing theory that intracellular fumarate activates nuclear factor (erythroid-derived 2)-like 2(NRF2) through post-translational modification of its negative regulator. Kelch-like ECH-associated protein 1(KEAP1) has emerged from a computational modeling study and mouse model studies.  This review dissects the origin of these two governing theories and highlights the presence of chromatin-structure-regulated targets of transcription factors, which we refer to as "cryptic targets" of transcription factors.  One such cryptic target is heme oxygenase I(HMOX1), the expression of which is known to be modulated by the gene product of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1).
authors: Laboratory of Interdisciplinary Urological Oncology, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
authors: Aikseng
authors: A
authors: Ooi
authors: Kyle A
authors: KA
authors: Furge
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000378:metabolism; D005649:Fumarate Hydratase / Q000235:genetics* / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D018231:Leiomyomatosis / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012878:Skin Neoplasms; D014157:Transcription Factors / Q000378:metabolism; D014594:Uterine Neoplasms
chemical_list: D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D011393:Procollagen-Proline Dioxygenase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D005649:Fumarate Hydratase