Primary Cilium Regulates CaV1.2 Expression Through Wnt Signaling

Muntean, Brian S.; Jin, Xingjian; Williams, Frederick; Nauli, Surya M.

doi:10.1002/jcp.24642

Cited by 16 publications

(17 citation statements)

References 34 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lentivirus was harvested at 48 and 72 hours after the initial transfection. The titration was determined to be ~10 7 with the method described previously [18,19]. One ml of each shRNA-lentivirus was added to cells grown on the 10-cm cell culture dishes.…”

Section: Methodsmentioning

confidence: 99%

L-type calcium channel modulates cystic kidney phenotype

Jin

Muntean

Aal-Aaboda

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Self Cite

View full text Add to dashboard Cite

In polycystic kidney disease (PKD), abnormal proliferation and genomic instability of renal epithelia have been associated with cyst formation and kidney enlargement. We recently showed that L-type calcium channel (Cav1.2) is localized to primary cilia of epithelial cells. Previous studies have also shown that low intracellular calcium level was associated with the hyperproliferation phenotype in the epithelial cells. However, the relationship between calcium channel and cystic kidney phenotype is largely unknown. In this study, we generated cells with somatic deficient Pkd1 or Pkd2 to examine ciliary CaV1.2 function via lentiviral knockdown or pharmacological verapamil inhibition. Although inhibition of CaV1.2 expression or function did not change division and growth patterns in wild-type epithelium, it led to hyperproliferation and polyploidy in mutant cells. Lack of CaV1.2 in Pkd mutant cells also decreased the intracellular calcium level. This contributed to a decrease in CaM kinase activity, which played a significant role in regulating Akt and Erk signaling pathways. Consistent with our in vitro results, CaV1.2 knockdown in zebrafish and Pkd1 heterozygous mice facilitated the formation of kidney cysts. Larger cysts were developed faster in Pkd1 heterozygous mice with CaV1.2 knockdown. Overall, our findings emphasized the importance of CaV1.2 expression in kidneys with somatic Pkd mutation. We further suggest that CaV1.2 could serve as a modifier gene to cystic kidney phenotype.

show abstract

Section: Methodsmentioning

confidence: 99%

L-type calcium channel modulates cystic kidney phenotype

Jin

Muntean

Aal-Aaboda

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Self Cite

View full text Add to dashboard Cite

show abstract

“…Primary cilia regulates cellular homeostasis through Wntsignaling (31). Moreover, the primary cilium integrates Hedgehog and Wnt signaling between dental epithelia and mesenchyme during the proper tooth development (32).…”

Section: Discussionmentioning

confidence: 99%

Wnt Signaling Inhibits the Growth of Primary Cilia and Activates CyclinD1, Snail and VEGFA Expression in Breast Cancer Cell Line MDA-MB-231

Deng¹

2015

AJLS

View full text Add to dashboard Cite

Abstract:Although Wnt/β-catenin signaling has been shown to be essential in the process of cancer formation, it is unclear how Wnt3a signaling pathway regulates abnormal proliferation and differentiation of breast cancer cells. Here, we found overexpression of Wnt3a stimulated the expression of the Wntsignaling's downstream genes such as LRP6, Naked, Axin1, DVL-2, β-catenin, and TCF-1 in breast cancer cell line MDA-MB-231.Primarycilia is deemed as sensory cell antennae thatcoordinates a large number of cellular signaling pathways, sometimes coupling cell division and differentiation. Primary cilia were found on the surface of this cell line. Overexpression of Wnt3a decreased the formation of primary cilia. Inhibition of Wnt3a with Calphostin C facilitated growth of primary cilia. Wnt3a activated cell proliferation gene of CyclinD1. In contrary, Calphostin C decreased the promotional effect on proliferation of MDA-MB-231. The Snail family of transcription factor has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transitions) during embryonic development. Wnt3a promoted MDA-MB-231 induced expression of Snail, whose effect was inhibited by Calphostin-C. VEGFA activity was originally referred to as vascular permeability factor and had been shown to stimulate endothelial cell mitogenesis and cell migration and increased microvascular permeability. Wnt3a facilitated MDA-MB-231 induced expression of VEGFA, as well as Calphostin-C suppressed its effect. Taken together, these results suggested thatWnt3a signaling played an important role in regulating the formation of breast cancer.

show abstract

“…Nauli's laboratory has recently shown that the L-type calcium channel modulates cystic kidney phenotype, hydrocephalus, and left-right asymmetry defects (74, 75). L-type calcium channel knockdown in zebrafish facilitates the formation of these ciliopathic phenotypes.…”

Section: Ciliary Calcium Channelsmentioning

confidence: 99%

“…This further reiterates the importance of calcium signaling in the chemosensory roles of primary cilia. The primary cilium also regulates L-type calcium channel expression through Wnt signaling (75). Suppressed Wnt signaling prevents CaV1.2 expression, ultimately resulting in the phenotypes of polycystic kidney disease.…”

Section: Ciliary Calcium Channelsmentioning

confidence: 99%

Calcium channels in primary cilia

Nauli

Pala

Kleene

2016

Current Opinion in Nephrology and Hypertension

Self Cite

View full text Add to dashboard Cite

Purpose of review Primary cilia have become important organelles implicated in embryonic development, organogenesis, health, and diseases. While many studies in cell biology have focused on changes in ciliary length or ciliogenesis, the most common readout for evaluating ciliary function is intracellular calcium. Recent findings Recent tools have allowed us to examine intracellular calcium in more precise locations, i.e. the cilioplasm and cytoplasm. Advances in calcium imaging have also allowed us to identify which cilia respond to particular stimuli. Furthermore, direct electrophysiological measurement of ionic currents within a cilium has provided a wealth of information for understanding the sensory roles of primary cilia. Summary Calcium imaging and direct measurement of calcium currents demonstrate that primary cilia are sensory organelles that house several types of functional calcium channels. Although intracellular calcium now allows a functional read-out for primary cilia, discussions on the relative contributions of the several channel types have just begun. Perhaps all of these calcium channels are required and necessary to differentiate stimuli in different microenvironments.

show abstract

Primary Cilium Regulates CaV1.2 Expression Through Wnt Signaling

Cited by 16 publications

References 34 publications

L-type calcium channel modulates cystic kidney phenotype

L-type calcium channel modulates cystic kidney phenotype

Wnt Signaling Inhibits the Growth of Primary Cilia and Activates CyclinD1, Snail and VEGFA Expression in Breast Cancer Cell Line MDA-MB-231

Calcium channels in primary cilia

Contact Info

Product

Resources

About