Early Embryonic Lethality Caused by Disruption of the Gene for Choline Kinase α, the First Enzyme in Phosphatidylcholine Biosynthesis

Wu, Gengshu; Aoyama, Chieko; Young, Stephen G.; Vance, Dennis E.

doi:10.1074/jbc.m708766200

Cited by 90 publications

(71 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Homozygous knockout of CHKA in mice results in embryonic lethality at the blastocyst stage (Wu et al, 2008), whereas upregulation of CHKA activity, or increased abundance of choline/PCho is commonly observed in cancer (Glunde et al, 2008;Hernando et al, 2009;Miyake and Parsons, 2012). CHKA is required for growth-factor-induced cellular proliferation in primary human mammary epithelial cells (Ramírez de Molina et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

George

Purdue

Gould

et al. 2013

Journal of Cell Science

View full text Add to dashboard Cite

SummaryThe angiotensin type 1 receptor (AT 1 R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT 1 R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT 1 R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT 1 R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT 1 R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

George

Purdue

Gould

et al. 2013

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…CKa is highly expressed in testis and liver, whereas CKb is abundant in heart and liver. Gene disruption of Chka in mice caused embryonic lethality, highlighting the importance of CKa for development (37). A spontaneous recessive mutation in the Chkb gene was identified in mice that unexpectedly led to progressive muscular dystrophy and neonatal bone deformity (38).…”

Section: Ckmentioning

confidence: 99%

Physiological consequences of disruption of mammalian phospholipid biosynthetic genes

Vance

2009

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

By 1959, Eugene Kennedy and coworkers had outlined most pathways of phospholipid biosynthesis. In the next four decades, the emphasis was on enzymology and regulation of these pathways. In the last 12 years, several lines of mice with disrupted genes of phospholipid biosynthesis were generated. From this research, we have learned that embryonic lethality occurs in mice that lack choline kinase (CK) a, CTP:phosphocholine cytidylyltransferase a, CTP:phosphoethanolamine cytidylyltransferase, or phosphatidylserine decarboxylase. Whereas mice that lack CK b are viable but develop hindlimb muscular dystrophy and neonatal bone deformity. Mice that lack CTP:phosphocholine cytidylytransferase b have gonadal dysfunction and defective axon branching. Mice that lack phosphatidylethanolamine N-methyltransferase exhibit no phenotype until fed a choline-deficient diet, which leads to rapid liver failure. Future research should extend our knowledge about the function of these and other enzymes of phospholipid biosynthesis.-Vance, D. E., and J. E. Vance. Physiological consequences of disruption of mammalian phospholipid biosynthetic genes. J. Lipid Res. 2009. 50: S132-S137. Supplementary key words phosphatidylcholineIn 1959, the general outline of biosynthesis of major phospholipids had been established in studies pioneered by Eugene Kennedy (1-3). A key finding was that CTP, not ATP, was the ribonucleoside triphosphate required for phospholipid biosynthesis (1). The next major focus was to purify enzymes involved in phospholipid biosynthesis, many of which were integral membrane proteins. Thus, success was limited. Choline kinase (CK) was purified in 1984 (4), CTP:phosphocholine cytidylyltransferase (CT) was purified in 1987 (5), and the integral membrane protein, phosphatidylethanolamine (PE) N-methyltransferase (PEMT) that converts PE to PC was purified in 1987 (6). Several phospholipid biosynthetic enzymes have never been purified.In the 1970s, investigations into the regulation of phospholipid biosynthesis were initiated. In 1975, primary rat hepatocytes were used to demonstrate that the second enzyme in the Kennedy pathway for PC biosynthesis, CT, catalyzed the rate-limiting step (7). These findings were confirmed under most metabolic conditions (8). In addition, the rate-limiting enzyme of PE synthesis via CDP-ethanolamine was identified as CTP:phosphoethanolamine cytidylyltransferase (ET) (7). A striking regulatory feature of PC biosynthesis is that CT is inactive in the cytosolic fraction of cells but is activated by translocation to membranes (9). Insights into the mechanism of translocation of CT to membranes have been largely provided by Cornell and Northwood (10) and Taneva et al. (11). Studies on regulation of expression of mRNAs encoding CTa have concluded that CTa expression is linked to the cell cycle, cell growth, and differentiation rather than energy metabolism (12).Clearly, significant progress has been made during the last 50 years in understanding the enzymology and regulation of PC biosynthesis. ...

show abstract

“…CKb is encoded by Chkb, which is located on chromosome 15. Mice that do not express either CKa isoform die at an early stage of embryogenesis, around day 3 (17). Mice that lack CKb are viable but develop rostrocaudal muscular dystrophy and neonatal bone deformity (18).…”

Section: Choline Kinasementioning

confidence: 99%

Thematic Review Series: Glycerolipids. Phosphatidylcholine and choline homeostasis

Vance

2008

Journal of Lipid Research

Self Cite

529

240

View full text Add to dashboard Cite

Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Animals obtain choline primarily from the diet or from the conversion of phosphatidylethanolamine (PE) to PC followed by catabolism to choline. The main fate of choline is the synthesis of PC. In addition, choline is oxidized to betaine in kidney and liver and converted to acetylcholine in the nervous system. Mice that lack choline kinase (CK) a die during embryogenesis, whereas mice that lack CKb unexpectedly develop muscular dystrophy. Mice that lack CTP:phosphocholine cytidylyltransferase (CT) a also die during early embryogenesis, whereas mice that lack CTb exhibit gonadal dysfunction. The cytidylyltransferase b isoform also plays a role in the branching of axons of neurons. An alternative PC biosynthetic pathway in the liver uses phosphatidylethanolamine N-methyltransferase to catalyze the formation of PC from PE. Mice that lack the methyltransferase survive but die from steatohepatitis and liver failure when placed on a choline-deficient diet. Hence, choline is an essential nutrient. PC biosynthesis is required for normal very low density lipoprotein secretion from hepatocytes. Recent studies indicate that choline is recycled in the liver and redistributed from kidney, lung, and intestine to liver and brain when choline supply is attenuated.-Li, Z., and D. E. Vance.Phosphatidylcholine and choline homeostasis.

show abstract

Early Embryonic Lethality Caused by Disruption of the Gene for Choline Kinase α, the First Enzyme in Phosphatidylcholine Biosynthesis

Cited by 90 publications

References 46 publications

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

Physiological consequences of disruption of mammalian phospholipid biosynthetic genes

Thematic Review Series: Glycerolipids. Phosphatidylcholine and choline homeostasis

Contact Info

Product

Resources

About