Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Bianchi, F.; Tocco, Chiara; Pallavicini, Gianmarco; Liu, Yifan; Vernı̀, Fiammetta; Merigliano, Chiara; Bonaccorsi, Silvia; El-Assawy, Nadia; Priano, Lorenzo; Gai, Marta; Berto, Gaia; Chiotto, Alessandra M.A.; Sgrò, Francesco; Caramello, Alessia; Tasca, Laura; Ala, Ugo; Neri, Francesco; Oliviero, Salvatore; Mauro, Alessandro; Geley, Stephan; Gatti, Maurizio; Cunto, Ferdinando Di

doi:10.1016/j.celrep.2017.01.054

Cited by 54 publications

(96 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fixed slices were imaged using a PL APO x40/1.2 NA oil immersion objective (Bianchi et al . ). All the images were analysed by using Fiji software.…”

Section: Methodsmentioning

confidence: 97%

Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2‐neo mouse rescued by L‐type calcium channel blockers

Calorio

Gavello

Guarina

et al. 2019

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

Key points Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de novo point mutation in the gene encoding the Cav1.2 (CACNA1C) L‐type channel. To study the role of Cav1.2 channel signals in autism, the autistic TS2‐neo mouse has been generated bearing the G406R point‐mutation associated with TS type‐2. Using heterozygous TS2‐neo mice, we report that the G406R mutation reduces the rate of inactivation and shifts leftward the activation and inactivation of L‐type channels, causing marked increase of resting Ca2+ influx (‘window’ Ca2+ current). The increased ‘window current’ causes marked reduction of NaV channel density, switches normal tonic firing to abnormal burst firing, reduces mitochondrial metabolism, induces cell swelling and decreases catecholamine release. Overnight incubations with nifedipine rescue NaV channel density, normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cell malfunction derives from altered Cav1.2 channel gating. Abstract L‐type voltage‐gated calcium (Cav1) channels have a key role in long‐term synaptic plasticity, sensory transduction, muscle contraction and hormone release. A point mutation in the gene encoding Cav1.2 (CACNA1C) causes Tymothy syndrome (TS), a multisystem disorder featuring cardiac arrhythmias, autism spectrum disorder (ASD) and adrenal gland dysfunction. In the more severe type‐2 form (TS2), the missense mutation G406R is on exon 8 coding for the IS6‐helix of the Cav1.2 channel. The mutation causes reduced inactivation and induces autism. How this occurs and how Cav1.2 gating‐changes alter cell excitability, neuronal firing and hormone release on a molecular basis is still largely unknown. Here, using the TS2‐neo mouse model of TS we show that the G406R mutation altered excitability and reduced secretory activity in adrenal chromaffin cells (CCs). Specifically, the TS2 mutation reduced the rate of voltage‐dependent inactivation and shifted leftward the activation and steady‐state inactivation of L‐type channels. This markedly increased the resting ‘window’ Ca2+ current that caused an increased percentage of CCs undergoing abnormal action potential (AP) burst firing, cell swelling, reduced mitochondrial metabolism and decreased catecholamine release. The increased ‘window’ Ca2+ current caused also decreased NaV channel density and increased steady‐state inactivation, which contributed to the increased abnormal burst firing. Overnight incubation with the L‐type channel blocker nifedipine rescued the normal AP firing of CCs, the density of functioning NaV channels and their steady‐state inactivation. We provide evidence that CC malfunction derives from the altered Cav1.2 channel gating and that dihydropyridines are potential therapeutics for ASD.

show abstract

“…Fixed slices were imaged using a PL APO x40/1.2 NA oil immersion objective (Bianchi et al . ). All the images were analysed by using Fiji software.…”

Section: Methodsmentioning

confidence: 97%

Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2‐neo mouse rescued by L‐type calcium channel blockers

Calorio

Gavello

Guarina

et al. 2019

The Journal of Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Finally, we have also shown that actively dividing and polyploid cancer cells are more susceptible to CIT-K depletion, suggesting that targeting CIT-K is a promising anti-cancer therapeutic approach for a wide range of cancers, especially those that are characterized by rapid cell proliferation and polyploidy ( . However, it is important to note that CIT-K loss can cause CIN owing to its involvement in DNA damage control and independently of its role in cytokinesis (Bianchi et al, 2017). This raises the possibility that the effects on cancer cells upon CIT-K depletion result from a combination of cytokinesis failure and increased DNA damage.…”

Section: Cit-k and Diseasementioning

confidence: 99%

“…Last, there is evidence that CIT-K has other roles besides in cell division. In addition to its recently described role in DNA damage (Bianchi et al, 2017), CIT-K has also been proposed to function in virus budding, organization of the Golgi complex and epigenetic gene silencing (Camera et al, 2003;Ding et al, 2016;Loomis et al, 2006;Sweeney et al, 2008) but, as yet, there are no major insights into its mechanisms of action in these processes.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Citron kinase – renaissance of a neglected mitotic kinase

D’Avino

2017

Journal of Cell Science

View full text Add to dashboard Cite

Cell division controls the faithful segregation of genomic and cytoplasmic materials between the two nascent daughter cells. Members of the Aurora, Polo and cyclin-dependent (Cdk) kinase families are known to regulate multiple events throughout cell division, whereas another kinase, citron kinase (CIT-K), for a long time has been considered to function solely during cytokinesis, the last phase of cell division. CIT-K was originally proposed to regulate the ingression of the cleavage furrow that forms at the equatorial cortex of the dividing cell after chromosome segregation. However, studies in the last decade have clarified that this kinase is, instead, required for the organization of the midbody in late cytokinesis, and also revealed novel functions of CIT-K earlier in mitosis and in DNA damage control. Moreover, CIT-K mutations have recently been linked to the development of human microcephaly, and CIT-K has been identified as a potential target in cancer therapy. In this Commentary, I describe and re-evaluate the functions and regulation of CIT-K during cell division and its involvement in human disease. Finally, I offer my perspectives on the open questions and future challenges that are necessary to address, in order to fully understand this important and yet unjustly neglected mitotic kinase.

show abstract

“…Apoptosis of neuronal progenitors [76,77] Cell cycle and apoptosis (colon cancer, CC) [26] DNA damage, proliferation, cell senescence and apoptosis (medulloblastoma) [33] MCPH18 (WDFY3)…”

Section: Mcph17 (Cit)mentioning

confidence: 99%

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

Zhou

Zhi

et al. 2020

IJMS

View full text Add to dashboard Cite

The stem cells of neurogenesis and carcinogenesis share many properties, including proliferative rate, an extensive replicative potential, the potential to generate different cell types of a given tissue, and an ability to independently migrate to a damaged area. This is also evidenced by the common molecular principles regulating key processes associated with cell division and apoptosis. Autosomal recessive primary microcephaly (MCPH) is a neurogenic mitotic disorder that is characterized by decreased brain size and mental retardation. Until now, a total of 25 genes have been identified that are known to be associated with MCPH. The inactivation (yin) of most MCPH genes leads to neurogenesis defects, while the upregulation (yang) of some MCPH genes is associated with different kinds of carcinogenesis. Here, we try to summarize the roles of MCPH genes in these two diseases and explore the underlying mechanisms, which will help us to explore new, attractive approaches to targeting tumor cells that are resistant to the current therapies.

show abstract

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Cited by 54 publications

References 62 publications

Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2‐neo mouse rescued by L‐type calcium channel blockers

Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2‐neo mouse rescued by L‐type calcium channel blockers

Citron kinase – renaissance of a neglected mitotic kinase

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

Contact Info

Product

Resources

About