Mutations in <i>SOX9</i> cause both autosomal sex reversal and campomelic dysplasia

Foster, Jamie W.

doi:10.1111/j.1442-200x.1996.tb03515.x

Cited by 63 publications

(38 citation statements)

References 24 publications

(4 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, Sox9 is sufficient to initiate chondrogenic programs when activated in mesenchymal stem cells (Ikeda et al, 2004), embryonic stem cells (Ikeda et al, 2004) and human dermal fibroblasts (Ikeda et al, 2004;Ohba et al, 2015;Outani et al, 2013). Inactivating mutations in human SOX9 result in campomelic dysplasia, an autosomal dominant disorder characterized by hypoplasia of the endochondral skeleton and bowing of skeletal elements (Foster, 1996;Giordano et al, 2001;Kwok et al, 1995). Molecular studies indicate that Sox9 promotes expression of a broad spectrum of cartilage matrix components, promotes cell division and cell survival, and inhibits chondrocytes from adopting an alternative pathway of osteoblast development (reviewed by Lefebvre and Dvir-Ginzberg, 2016).…”

Section: Introductionmentioning

confidence: 99%

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

Ohba

Hojo

et al. 2016

Development

View full text Add to dashboard Cite

An analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif. Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun-and Sox9-bound regions throughout the chondrocyte genome, reflecting direct binding of each factor to the same enhancers and a potential for protein-protein interactions within AP-1-and Sox9-containing complexes. In vitro reporter analysis indicated that direct co-binding of Sox9 and AP-1 at target motifs promoted gene activity. By contrast, where only one factor can engage its DNA target, the presence of the other factor suppresses target activation consistent with protein-protein interactions attenuating transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 confirmed the requirement of Sox9 for hypertrophic chondrocyte development, and in vitro and ex vivo analyses showed that AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model in which AP-1 family members contribute to Sox9 action in the transition of chondrocytes to the hypertrophic program.

show abstract

Section: Introductionmentioning

confidence: 99%

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

Ohba

Hojo

et al. 2016

Development

View full text Add to dashboard Cite

show abstract

“…SOX9 [SRY (sex determining region Y)-box 9] was originally identified as a factor necessary for development of the testis (2). SOX9 acts as a transcription factor, binding to a defined consensus sequence (3,4).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Čamaj

Jäckel

Krebs

et al. 2014

Molecular Cancer Research

View full text Add to dashboard Cite

Pancreatic cancer aggressiveness is characterized by its high capacity for local invasion, ability to promote angiogenesis, and potential to metastasize. Hypoxia is known to represent a crucial step in the development of aggressive malignant features of many human cancers. However, micrometastatic tumors are not typically subjected to hypoxic events during early stages of dissemination; therefore, it is unclear how these tumors are able to maintain their aggressive phenotype. Thus, the identification of regulators of hypoxia-related genes in aggressive/ metastatic tumors represents a fundamental step for the design of future therapies to treat pancreatic cancer. To this end, transcriptomic profiles were compared between the nonmetastatic pancreatic cancer cell line FG (LMET) and its angiogenic/metastatic derivate L3.6pl (HMET) under normoxic or hypoxic conditions. Cluster analysis revealed a number of transcripts that were induced by hypoxia in nonmetastatic cancer cells. Strikingly, this cluster was determined to be constitutively activated under normoxia in the metastatic cancer cells and could not be further induced by hypoxia. A subset of these transcripts were regulated by the transcription factor SOX9 in the aggressivemetastatic cells, but driven by hypoxia-inducible factor-1a (HIF-1a) in the parental nonmetastatic cell line. Moreover, these transcripts were enriched in cancer-related networks including: WNT, CXCR4, retinoic acid, and (FAK) focal adhesion kinase, gene PTK2 signaling pathways. In functional assays, inhibition of SOX9 expression in HMET cells led to increased apoptosis and reduced migration in vitro and a significant reduction in primary tumor growth, angiogenesis, and metastasis following orthotopic tumor cell injection. At the molecular level, the control of SOX9 expression was associated with changes in the methylation status of the SOX9 promoter. Finally, SOX9 upregulation was verified in a series of tumor specimens of patients with pancreatic carcinoma.

show abstract

“…Heterozygous SOX9 mutations are the cause of the human disease campomelic dysplasia, a form of dwarfism characterized by extreme cartilage and bone malformation, which is frequently associated with XY sex reversal and other anomalies (24)(25)(26)(27). Homozygous knockout of SOX9 in mice results in embryonic lethality, whereas SOX9 heterozygous knockouts exhibit the same skeletal anomalies as campomelic dysplasia patients (28,29).…”

Section: Introductionmentioning

confidence: 99%

SOX9 Is Expressed in Normal Prostate Basal Cells and Regulates Androgen Receptor Expression in Prostate Cancer Cells

Wang¹,

McKnight²,

Zhang³

et al. 2007

Cancer Research

125

136

View full text Add to dashboard Cite

SOX9 is a member of the SOX [Sry-related high-mobility group (HMG) box] family of HMG DNA-binding domain transcription factors and is required for the development and differentiation of multiple cell lineages. This report shows that basal epithelial cells express SOX9 in normal prostate, with no detectable expression in luminal epithelial cells. In contrast, SOX9 is expressed in primary prostate cancers in vivo, at a higher frequency in recurrent prostate cancer and in prostate cancer cell lines (LNCaP, CWR22, PC3, and DU145). SOX9 message and protein levels in prostate cancer cells were increased by treatment with glycogen synthase kinase 3B inhibitor (SB415286), and SOX9 was reduced when B-catenin was downregulated by small interfering RNA (siRNA), indicating that SOX9 expression in prostate cancer is regulated by Wnt/Bcatenin signaling. SOX9 bound specifically to androgen receptor (AR) DNA-binding domain glutathione S-transferase fusion proteins, and this interaction was dependent on a short peptide immediately COOH-terminal to the DNA-binding domain (the C-terminal extension), which is required for interactions between steroid hormone receptors and the architectural HMG proteins. Exogenous SOX9 expressed at high nonphysiologic levels decreased AR expression and activity; however, at lower levels, SOX9 increased AR protein expression. Significantly, down-regulation of SOX9 by siRNA in prostate cancer cells reduced endogenous AR protein levels, and cell growth indicating that SOX9 contributes to AR regulation and decreased cellular proliferation. These results indicate that SOX9 in prostate basal cells supports the development and maintenance of the luminal epithelium and that a subset of prostate cancer cells may escape basal cell requirements through SOX9 expression. [Cancer Res 2007;67(2):528-36]

show abstract

Mutations in SOX9 cause both autosomal sex reversal and campomelic dysplasia

Cited by 63 publications

References 24 publications

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

SOX9 Is Expressed in Normal Prostate Basal Cells and Regulates Androgen Receptor Expression in Prostate Cancer Cells

Contact Info

Product

Resources

About