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1.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Article in English | MEDLINE | ID: mdl-33443141

ABSTRACT

Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.


Subject(s)
DNA Damage/genetics , Nucleic Acid Amplification Techniques/methods , Transcription, Genetic/genetics , DNA Repair/genetics , DNA Replication/genetics , Humans , Mutagenesis/genetics , Mutagenesis/physiology , Mutagens/toxicity , Mutation/genetics
2.
Oncogene ; 32(22): 2739-46, 2013 May 30.
Article in English | MEDLINE | ID: mdl-22797072

ABSTRACT

Ovarian granulosa cell tumors (OGCT) are the most frequent kind of sex cord-stromal tumors, and represent ∼2-5% of all ovarian malignancies. OGCTs exist as two entities, juvenile and adult types, with specific clinical and pathological characteristics. The molecular pathogenesis of these tumors has just begun to be unraveled. Indeed, recent studies have indicated that mutation and/or misregulation of the key ovarian transcription factor FOXL2 has a role in OGCT formation, although the mechanisms remain unclear. To better understand the molecular characteristics of OGCT, we studied the transcriptomic profiles of ten human adult-type OGCT samples, as well as ethnically matched granulosa cell (GC) controls. We find that the OGCT samples analyzed herein exhibit several hallmarks of cancer, including increased expression of genes linked to cell proliferation, but decreased expression of those conferring sensitivity to cell death. Moreover, genes differentially expressed in OGCTs are significantly enriched for known FOXL2 target genes, consistently with the prevalence of FOXL2 somatic mutation in these tumors. Expression of these targets is altered in a way expected to promote malignant transformation, for instance, through induction of genes associated with faster cell cycling and downregulation of genes associated with cell death. Over time, such defects may be responsible at least partly for the malignant transformation of healthy GCs into OGCT. These insights into the molecular pathogenesis of OGCTs may open the way to new efforts in the development of more targeted therapeutic strategies for OGCT patients.


Subject(s)
Forkhead Transcription Factors/genetics , Granulosa Cell Tumor/genetics , Ovarian Neoplasms/genetics , Adult , Aged , Cell Line, Tumor , Cell Proliferation , Female , Forkhead Box Protein L2 , Gene Expression Profiling , Granulosa Cells/metabolism , Granulosa Cells/pathology , HeLa Cells , Humans , Middle Aged , Mutation , Ovary/pathology , Transcriptome/genetics
3.
J Med Genet ; 46(7): 455-7, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19429596

ABSTRACT

BACKGROUND: FOXL2 encodes a forkhead transcription factor whose mutations are responsible for the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), involving craniofacial/palpebral abnormalities often associated with premature ovarian failure (POF). RESULTS: We describe a FOXL2 variant (p.Gly187Asp) in a case of POF without BPES. The subcellular localisation of FOXL2-G187D was normal but its transactivation capacity tested on two reporter promoters, one of which should be relevant to the ovary, was significantly lower than that of normal FOXL2. However, FOXL2-G187D was able to activate strongly a reporter construct driven by the promoter of Osr2 (odd-skipped related 2 transcription factor), which we have suggested to be a crucial target of FOXL2 in the craniofacial region. This is compatible with the absence of BPES in our patient. CONCLUSIONS: Our data provide evidence in favour of the implication of FOXL2 variants in non-syndromic POF and confirm the regulatory interaction between FOXL2 and OSR2 whose perturbation might contribute to the palpebral abnormalities observed in BPES patients.


Subject(s)
Forkhead Transcription Factors/genetics , Gene Expression Regulation , Primary Ovarian Insufficiency/genetics , Transcription Factors/genetics , Adult , Amino Acid Sequence , Amino Acid Substitution , Animals , Female , Forkhead Box Protein L2 , Humans , Molecular Sequence Data , Mutation , Promoter Regions, Genetic , Sequence Alignment
4.
Mol Cell Endocrinol ; 282(1-2): 2-11, 2008 Jan 30.
Article in English | MEDLINE | ID: mdl-18155828

ABSTRACT

Mutations of FOXL2, a gene encoding a forkhead transcription factor, have been shown to cause the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). This genetic disorder is characterized by eyelid and mild craniofacial abnormalities that can appear associated with premature ovarian failure. FOXL2 is one of the earliest ovarian markers and it offers, along with its targets, an excellent model to study ovarian development and function in normal and pathological conditions. In this review we summarize recent data concerning FOXL2, its mutations and its potential targets. Indeed, many mutations have been described in the coding sequence of FOXL2. Among them, polyalanine expansions and premature nonsense mutations have been shown to induce protein aggregation. In the context of the ovary, FOXL2 has been suggested to be involved in the regulation of cholesterol and steroid metabolism, apoptosis, reactive oxygen species detoxification and inflammation processes. The elucidation of the impact of FOXL2 mutations on its function will allow a better understanding of the pathogenic mechanisms underlying the BPES phenotype.


Subject(s)
Forkhead Transcription Factors/genetics , Mutation/genetics , Animals , Blepharophimosis/physiopathology , Blepharoptosis/physiopathology , Craniofacial Abnormalities/physiopathology , Disorders of Sex Development , Female , Forkhead Box Protein L2 , Forkhead Transcription Factors/physiology , Humans , Mice , Mice, Transgenic , Ovary/physiopathology , Syndrome
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