Ca
            <sub>v</sub>
            3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Lin, Szu-Yin; Tzeng, Bing-Hsiean; Lee, Kuan‐Rong; Smith, Richard J.H.; Campbell, Kevin P.; Chen, Chien‐Chang

doi:10.1073/pnas.1323112111

Cited by 56 publications

(41 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is interesting that our chondrocyte Bmal1-cKO mice showed profound and progressive lesions in the articular cartilage that were not found in global Bmal1-KO mice (22). The articular cartilage was reportedly normal in global Bmal1-KO Consistent with earlier reports on NFAT-mediated regulation of Sox9 (35,36), protein levels of SOX9 were concomitantly reduced in cKO knee cartilage ( Figure 6, B and C). Significant reductions of Sox9, Acan, and Col2a1 mRNA in cKO cartilage were observed at the 2 night time points ( Figure 6D).…”

Section: Discussionsupporting

confidence: 89%

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Dudek¹,

Gossan²,

Yang³

et al. 2015

Journal of Clinical Investigation

169

202

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 89%

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Dudek¹,

Gossan²,

Yang³

et al. 2015

Journal of Clinical Investigation

169

202

View full text Add to dashboard Cite

“…As mentioned before, the T-type CaV3.2 was the first VDCC shown to be indispensable for tracheal chondrogenesis both in vivo and in vitro [40]. These findings were substantiated by the fact that mice lacking CaV3.2 showed congenital tracheal stenosis; conversely, Cav3.2 over-expression in ATDC5 cells augmented chondrogenesis.…”

Section: Vdccs Are Required For Chondrogenesismentioning

confidence: 54%

“…Although the above studies showed the presence of functional α1 subunits in mature or differentiating chondrocytes, CaV3.2 was the first α1 subunit identified as essential for tracheal chondrogenesis in mice; in mice lacking CaV3.2 channels, Sox9 expression was attenuated, accompanied by disturbed tracheal cartilage formation [40].…”

Section: Subunit-specific Expression Of Vdcc: α1 Subunitsmentioning

confidence: 96%

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

2015

View full text Add to dashboard Cite

Chondrocytes, the single cell type in adult articular cartilage, have conventionally been considered to be non-excitable cells. However, recent evidence suggests that their resting membrane potential (RMP) is less negative than that of excitable cells, and they are fully equipped with channels that control ion, water, and osmolyte movement across the chondrocyte membrane. Among calcium-specific ion channels, members of the voltage-dependent calcium channel (VDCC) family are expressed in chondrocytes where they are functionally active. Ltype VDCC inhibitors such as nifedipine and verapamil have contributed to our understanding of the roles of these ion channels in chondrogenesis, chondrocyte signalling, and mechanotransduction. In this narrative review, we discuss published data indicating that VDCC function is vital for chondrocyte health, especially in regulating proliferation and maturation.We also highlight the fact that activation of VDCC function appears to accompany various inflammatory aspects of osteoarthritis (OA) and, based on in vitro data, the application of nifedipine and/or verapamil may be a promising approach for ameliorating OA severity.However, very few studies on clinical outcomes are available regarding the influence of calcium antagonists, which are used primarily for treating cardiovascular conditions in OA patients. This review is intended to stimulate further research on the chondrocyte 'channelome', contribute to the development of novel therapeutic strategies, and facilitate the retargeting and repositioning of existing pharmacological agents currently used for other comorbidities for the treatment of OA.

show abstract

“…The identification of Sox9 as a direct target gene of NFATc1 in pancreatic carcinogenesis is also supported by results from a recently published genome-wide ChIP-Seq analysis showing a recruitment of NFATc1 to the Sox9 promoter in primary pancreatic tumor cells derived from Kras G12D ;NFATc1 mice 22 . The activation of the NFATc1-Sox9 axis is not restricted to epithelial regeneration or cancer initiation since recent work identified NFATc1 recruitment to the Sox9 promoter during tracheal cartilage development 47 .…”

Section: Discussionmentioning

confidence: 99%

NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar–Ductal Transdifferentiation in the Pancreas

Chen¹,

Singh

Köenig

et al. 2015

Gastroenterology

View full text Add to dashboard Cite

Background & Aims Oncogenic Kras mutation is a defining genetic alteration in pancreatic ductal adenocarcinoma (PDAC), but is not sufficient to promote cancer formation on ist own. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. In this study we sought to identify the underlying mechanisms which link EGFR signaling to Sox9 gene induction during acinar–ductal metaplasia (ADM), a transdifferentiation process that precedes pancreatic carcinogenesis. Methods We analyzed pancreatic tissues from KrasG12D;pdx1-Cre and KrasG12D;NFATc1Δ/Δ;pdx1-Cre mice after intraperitoneal administration of caerulein or dimethyl suloxide (controls). Pharmacological inhibition of NFATc1 activation was achieved by application of cyclosporin A. Induction of EGFR signaling and its effects on expression of NFATc1 or SOX9 were investigated by quantitative reverse transcription PCR, immunoblot, and immunohistochemical analyses of mouse and human tissues and acinar cell explants. Interactions between NFATc1 and partner proteins and effects on DNA binding or chromatin modifications were studied using co-immunoprecipitation and chromatin immunoprecipitation assays in acinar cell explants and mouse tissue. Results EGFR activation induced NFATc1 expression in metaplastic tissues from patients with chronic pancreatitis and in pancreatic tissues from KrasG12D mice and promoted complex-formation with c-Jun in dedifferentiating acinar cells, thereby stimulating the transcription of ductal gene signatures to provoke ADM. This process involved NFATc1:c-Jun-mediated activation of Sox9 transcription in converting acinar cells. Pharmacological inhibition of NFATc1 or disruption of the Nfatc1 gene inhibited EGFR-mediated induction of Sox9 transcription and blocked acinar–ductal transdifferentiation and pancreatic cancer initiation. Conclusion Our findings identify an EGFR-NFATc1-Sox9 signaling cascade as a critical mediator of inflammation-induced PDAC initiation and suggest that disruption of this pathway may offer a novel chemopreventive target for high-risk pancreatitis patients.

show abstract

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Cited by 56 publications

References 88 publications

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar–Ductal Transdifferentiation in the Pancreas

Contact Info

Product

Resources

About

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Cited by 56 publications

References 88 publications

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar–Ductal Transdifferentiation in the Pancreas

Contact Info

Product

Resources

About

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage