A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells

A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of Zmpste24-deficient mice. However, we don't know whether Icmt inactivation improves phenotypes in an authentic HGPS mouse model. Moreover, it is unknown whether pharmacologic targeting of ICMT would be tolerated by cells and produce similar cellular effects as genetic inactivation. Here, we show that knockout of Icmt improves survival of HGPS mice and restores vascular smooth muscle cell numbers in the aorta. We also synthesized a potent ICMT inhibitor called C75 and found that it delays senescence and stimulates proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS.

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Isoprenylcysteine carboxylmethyltransferase-based therapy for Hutchinson–Gilford progeria syndrome

10.1101/2020.07.23.217257 ◽

2020 ◽

Author(s):

Beatriz Marcos-Ramiro ◽

Ana Gil-Ordóñez ◽

Nagore I. Marín-Ramos ◽

Francisco J. Ortega-Nogales ◽

Moisés Balabasquer ◽

...

Keyword(s):

Experimental Models ◽

Premature Aging ◽

Nuclear Accumulation ◽

Therapeutic Approaches ◽

Mouse Cells ◽

New Treatment ◽

Isoprenylcysteine Carboxylmethyltransferase ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Potential Use

ABSTRACTProgerin is a mutant prelamin A variant that causes Hutchinson–Gilford progeria syndrome (HGPS, progeria), a rare genetic disease characterized by premature aging and death in childhood. Although several therapeutic approaches have been explored in experimental models, clinical trials have shown very limited benefits in HGPS patients. Here, we describe the development of UCM-13207, a new potent inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT) that reduces progerin nuclear accumulation and ameliorates the typical alterations in progeroid human and mouse cells. UCM-13207 also improves phenotypic anomalies and extends lifespan in progerin-expressing LmnaG609G/G609G mice. These results support the potential use of UCM-13207 as a new treatment for progeria.

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Activating the synthesis of progerin, the mutant prelamin A in Hutchinson–Gilford progeria syndrome, with antisense oligonucleotides

Human Molecular Genetics ◽

10.1093/hmg/ddp184 ◽

2009 ◽

Vol 18 (13) ◽

pp. 2462-2471 ◽

Cited By ~ 26

Author(s):

Loren G. Fong ◽

Timothy A. Vickers ◽

Emily A. Farber ◽

Christine Choi ◽

Ui Jeong Yun ◽

...

Keyword(s):

Antisense Oligonucleotides ◽

Prelamin A ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

Biochemical Society Transactions ◽

10.1042/bst0361389 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1389-1392 ◽

Cited By ~ 6

Author(s):

Gemma S. Beard ◽

Joanna M. Bridger ◽

Ian R. Kill ◽

David R.P. Tree

Keyword(s):

Drosophila Melanogaster ◽

Premature Aging ◽

Lamin A ◽

Wild Type ◽

Drosophila Model ◽

Numerous Cell ◽

Cellular Abnormalities ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Adult Drosophila

The laminopathy Hutchinson–Gilford progeria syndrome (HGPS) is caused by the mutant lamin A protein progerin and leads to premature aging of affected children. Despite numerous cell biological and biochemical insights into the basis for the cellular abnormalities seen in HGPS, the mechanism linking progerin to the organismal phenotype is not fully understood. To begin to address the mechanism behind HGPS using Drosophila melanogaster, we have ectopically expressed progerin and lamin A. We found that ectopic progerin and lamin A phenocopy several effects of laminopathies in developing and adult Drosophila, but that progerin causes a stronger phenotype than wild-type lamin A.

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An in vivo inflammatory loop potentiates KRAS blockade

10.1101/629139 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kristina A.M. Arendt ◽

Giannoula Ntaliarda ◽

Vasileios Armenis ◽

Danai Kati ◽

Christin Henning ◽

...

Keyword(s):

Interleukin 1Β ◽

Wild Type ◽

Poor Survival ◽

Murine Bone Marrow ◽

Chemokine Ligand ◽

Isoprenylcysteine Carboxylmethyltransferase ◽

Chemokine Ligand 2 ◽

Deficient Mice

ABSTRACTKRAS inhibitors perform inferior to other targeted drugs. To investigate a possible reason for this, we treated cancer cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1β signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Hence the findings support that in vitro systems are suboptimal for anti-KRAS drug screens, and suggest that interleukin-1β blockade might be specific for KRAS-mutant cancers.

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Lymphocyte–HEV Interactions in Lymph Nodes of a Sulfotransferase-deficient Mouse

Journal of Experimental Medicine ◽

10.1084/jem.20030057 ◽

2003 ◽

Vol 198 (9) ◽

pp. 1289-1300 ◽

Cited By ~ 36

Author(s):

Annemieke van Zante ◽

Jean-Marc Gauguet ◽

Annette Bistrup ◽

Durwin Tsay ◽

Ulrich H. von Andrian ◽

...

Keyword(s):

Lymph Nodes ◽

Dependent Manner ◽

Deficient Mouse ◽

Wild Type ◽

Lymphocyte Homing ◽

High Endothelial Venules ◽

Blocking Antibody ◽

Selectin Ligands ◽

Deficient Mice

The interaction of L-selectin expressed on lymphocytes with sulfated sialomucin ligands such as CD34 and GlyCAM-1 on high endothelial venules (HEV) of lymph nodes results in lymphocyte rolling and is essential for lymphocyte recruitment. HEC-GlcNAc6ST–deficient mice lack an HEV-restricted sulfotransferase with selectivity for the C-6 position of N-acetylglucosamine (GlcNAc). HEC-GlcNAc6ST−/− animals exhibit faster lymphocyte rolling and reduced lymphocyte sticking in HEV, accounting for the diminished lymphocyte homing. Isolated CD34 and GlyCAM-1 from HEC-GlcNAc6ST−/− animals incorporate ∼70% less sulfate than ligands from wild-type animals. Furthermore, these ligands exhibit a comparable reduction of the epitope recognized by MECA79, a function-blocking antibody that reacts with L-selectin ligands in a GlcNAc-6-sulfate–dependent manner. Whereas MECA79 dramatically inhibits lymphocyte rolling and homing to lymph nodes in wild-type mice, it has no effect on HEC-GlcNAc6ST−/− mice. In contrast, in vitro rolling on purified GlyCAM-1 from HEC-GlcNAc6ST−/− mice, although greatly diminished compared with that on the wild-type ligand, is inhibited by MECA79. Our results demonstrate that HEC-GlcNAc6ST contributes predominantly, but not exclusively, to the sulfation of HEV ligands for L-selectin and that alternative, non-MECA79–reactive ligands are present in the absence of HEC-GlcNAc6ST.

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Epidermal expression of the truncated prelamin A causing Hutchinson-Gilford progeria syndrome: effects on keratinocytes, hair and skin

Human Molecular Genetics ◽

10.1093/hmg/ddn136 ◽

2008 ◽

Vol 17 (15) ◽

pp. 2357-2369 ◽

Cited By ~ 31

Author(s):

Y. Wang ◽

A. A. Panteleyev ◽

D. M. Owens ◽

K. Djabali ◽

C. L. Stewart ◽

...

Keyword(s):

Prelamin A ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Epidermal Expression

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UV-induced mutations of supF gene on a shuttle vector plasmid in p53-deficient mouse cells are qualitatively different from those in wild-type cells

Mutation Research/DNA Repair ◽

10.1016/0921-8777(96)00020-1 ◽

1996 ◽

Vol 364 (1) ◽

pp. 43-49 ◽

Cited By ~ 5

Author(s):

Kanji Ishizaki ◽

Kimiko Nishizawa ◽

Sachiyo Mimaki ◽

Shin-ichi Aizawa

Keyword(s):

Shuttle Vector ◽

Deficient Mouse ◽

Wild Type ◽

Induced Mutations ◽

Vector Plasmid ◽

Mouse Cells ◽

Supf Gene

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ATP-based therapy prevents vascular calcification and extends longevity in a mouse model of Hutchinson–Gilford progeria syndrome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1910972116 ◽

2019 ◽

Vol 116 (47) ◽

pp. 23698-23704 ◽

Cited By ~ 13

Author(s):

Ricardo Villa-Bellosta

Keyword(s):

Mouse Model ◽

Vascular Calcification ◽

Therapeutic Approach ◽

Ex Vivo ◽

Combined Treatment ◽

Wild Type ◽

Extended Longevity ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Pyrophosphate Hydrolysis

Pyrophosphate deficiency may explain the excessive vascular calcification found in children with Hutchinson–Gilford progeria syndrome (HGPS) and in a mouse model of this disease. The present study found that hydrolysis products of ATP resulted in a <9% yield of pyrophosphate in wild-type blood and aortas, showing that eNTPD activity (ATP → phosphate) was greater than eNPP activity (ATP → pyrophosphate). Moreover, pyrophosphate synthesis from ATP was reduced and pyrophosphate hydrolysis (via TNAP; pyrophosphate → phosphate) was increased in both aortas and blood obtained from mice with HGPS. The reduced production of pyrophosphate, together with the reduction in plasma ATP, resulted in marked reduction of plasma pyrophosphate. The combination of TNAP inhibitor levamisole and eNTPD inhibitor ARL67156 increased the synthesis and reduced the degradation of pyrophosphate in aortas and blood ex vivo, suggesting that these combined inhibitors could represent a therapeutic approach for this devastating progeroid syndrome. Treatment with ATP prevented vascular calcification in HGPS mice but did not extend longevity. By contrast, combined treatment with ATP, levamisole, and ARL67156 prevented vascular calcification and extended longevity by 12% in HGPS mice. These findings suggest a therapeutic approach for children with HGPS.

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HCO 3 − reabsorption in renal collecting duct of NHE-3-deficient mouse: a compensatory response

AJP Renal Physiology ◽

10.1152/ajprenal.1999.276.6.f914 ◽

1999 ◽

Vol 276 (6) ◽

pp. F914-F921 ◽

Cited By ~ 14

Author(s):

Suguru Nakamura ◽

Hassane Amlal ◽

Patrick J. Schultheis ◽

John H. Galla ◽

Gary E. Shull ◽

...

Keyword(s):

Collecting Duct ◽

Mutant Mice ◽

Deficient Mouse ◽

Cortical Collecting Duct ◽

Wild Type ◽

Targeted Disruption ◽

Compensatory Response ◽

Enhanced Expression ◽

Medullary Collecting Duct ◽

Deficient Mice

Mice with a targeted disruption of Na+/H+exchanger NHE-3 gene show significant reduction in[Formula: see text] reabsorption in proximal tubule, consistent with the absence of NHE-3. Serum[Formula: see text], however, is only mildly decreased (P. Schulties, L. L. Clarke, P. Meneton, M. L. Miller, M. Soleimani, L. R. Gawenis, T. M. Riddle, J. J. Duffy, T. Doetschman, T. Wang, G. Giebisch, P. S. Aronson, J. N. Lorenz, and G. E. Shull. Nature Genet. 19: 282–285, 1998), indicating possible adaptive upregulation of[Formula: see text]-absorbing transporters in collecting duct of NHE-3-deficient (NHE-3 −/−) mice. Cortical collecting duct (CCD) and outer medullary collecting duct (OMCD) were perfused, and total CO2 (net[Formula: see text] flux, J tCO2) was measured in the presence of 10 μM Schering 28080 (SCH, inhibitor of gastric H+-K+-ATPase) or 50 μM diethylestilbestrol (DES, inhibitor of H+-ATPase) in both mutant and wild-type (WT) animals. In CCD, J tCO2increased in NHE-3 mutant mice (3.42 ± 0.28 in WT to 5.71 ± 0.39 pmol ⋅ min−1 ⋅ mm tubule−1 in mutants, P < 0.001). The SCH-sensitive net[Formula: see text] flux remained unchanged, whereas the DES-sensitive [Formula: see text] flux increased in the CCD of NHE-3 mutant animals. In OMCD, J tCO2increased in NHE-3 mutant mice (8.8 ± 0.7 in WT to 14.2 ± 0.6 pmol ⋅ min−1 ⋅ mm tubule−1 in mutants, P < 0.001). Both the SCH-sensitive and the DES-sensitive [Formula: see text] fluxes increased in the OMCD of NHE-3 mutant animals. Northern hybridizations demonstrated enhanced expression of the basolateral Cl−/[Formula: see text]exchanger (AE-1) mRNA in the cortex. The gastric H+-K+-ATPase mRNA showed upregulation in the medulla but not the cortex of NHE-3 mutant mice. Our results indicate that[Formula: see text] reabsorption is enhanced in CCD and OMCD of NHE-3-deficient mice. In CCD, H+-ATPase, and in the OMCD, both H+-ATPase and gastric H+-K+-ATPase contribute to the enhanced compensatory[Formula: see text] reabsorption in NHE-3-deficient animals.

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