Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition

Marji, Jackleen; O’Donoghue, Seán I.; McClintock, Dayle; Satagopam, Venkata; Schneider, Reinhard; Ratner, Désirée; Worman, Howard J.; Gordon, Leslie B.; Djabali, Karima

doi:10.1371/journal.pone.0011132

Cited by 65 publications

(59 citation statements)

References 42 publications

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“…4F–J). Previous literatures reported that releasing progerin from the nuclear membrane by farnesyltransferase inhibitor treatment partially rescued the gene expression and morphological defects in HGPS cells (Capell et al ., 2005, 2008; Capell & Collins, 2006; Gelb et al ., 2006; Cao et al ., 2007; Wang et al ., 2007; Marji et al ., 2010). Indeed, we find that not only the nuclear morphology but also the chromatin organization and gene expression are improved in the MB‐treated HGPS nucleus (Fig.…”

Section: Discussionmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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SummaryHutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

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Section: Discussionmentioning

confidence: 99%

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

et al. 2015

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“…LMNA binds directly to hypophosphorylated RB1 during the G 1 phase of the cell cycle and protects RB1 from proteasomal degradation (36). Gene expression profiling of HGPS fibroblasts also demonstrated that Rb1 mRNA levels are low in HGPS cells and that RB1 is the only known LMNA-interacting protein whose expression is abnormal compared with that of control cells (37). Results of additional studies using a farnesyltransferase inhibitor are consistent with the hypothesis that loss of RB1 is the primary direct effect of the LMNA mutation studied.…”

Section: Figurementioning

confidence: 98%

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Fu¹,

Landreville

Agapova

et al. 2013

J. Clin. Invest.

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The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development. To investigate the role of RB1 in neural crest-derived melanocytes, we bred mice with a floxed Rb1 allele with mice expressing Cre from the tyrosinase (Tyr) promoter. TyrCre + ;Rb1 fl/fl mice exhibited no melanocyte defects but died unexpectedly early with intestinal obstruction, striking defects in the enteric nervous system (ENS), and abnormal intestinal motility. Cre-induced DNA recombination occurred in all enteric glia and most small bowel myenteric neurons, yet phenotypic effects of Rb1 loss were cell-type specific. Enteric glia were twice as abundant in mutant mice compared with those in control animals, while myenteric neuron number was normal. Most myenteric neurons also appeared normal in size, but NO-producing myenteric neurons developed very large nuclei as a result of DNA replication without cell division (i.e., endoreplication). Parallel studies in vitro found that exogenous NO and Rb1 shRNA increased ENS precursor DNA replication and nuclear size. The large, irregularly shaped nuclei in NO-producing neurons were remarkably similar to those in progeria, an early-onset aging disorder that has been linked to RB1 dysfunction. These findings reveal a role for RB1 in the ENS. IntroductionChronic intestinal pseudo-obstruction (CIPO) is the clinical indication for 9 percent of small bowel transplants (1), yet the etiology for these disorders remains poorly understood. CIPO is diagnosed when bowel motility defects cause functional, but not mechanical, obstruction, leading to abdominal distension, pain, malnutrition, and, in severe cases, dependence on parenteral nutrition or intestinal transplantation for survival. It is likely that diverse genetic, infectious, autoimmune, metabolic, and toxic insults all contribute to CIPO etiology.Intestinal motility and many other aspects of bowel function are controlled by an interconnected intrinsic network of neurons and glia called the enteric nervous system (ENS) (2-4). The ENS forms from neural crest-derived cells that migrate through fetal bowel, proliferate extensively, and then exit the cell cycle and differentiate into many different neuronal subtypes (5-7). Defects in specific types of enteric neurons may cause life-threatening disease, and, like in the central nervous system, neurons in the ENS must be present in the proper ratios and with correct patterning for the bowel to work well. Signals that control ENS precursor proliferation and cell cycle exit are incompletely understood. Furthermore, the ENS can be damaged in many ways, often with preferential effects on NO-producing enteric neurons that inhibit bowel contraction (8). There are also regional differences in the susceptibility of enteric neurons to damage that are not well understood (9).We initially intended to develop a model of melanoma by deleting the tumor suppressor retinoblastoma 1 (Rb1) in melanocytes,

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“…Nuclear morphology is altered in laminopathies and is linked to lamin A and B defects (11)(12)(13)(14)(15). Lamins localize at the NE and maintain the nuclear shape; they also form dynamic invaginations that connect the NE with the cytoplasm and chromatin and regulate DNA events (2)(3)(4)(5)(6)(7)(8)41).…”

Section: Pi3k␤ Expression Is Necessary For Ne Integritymentioning

confidence: 99%

“…Nuclear lamina proteins interact with chromatin and with other proteins to regulate NE integrity as well as cell responses, such as cell cycle progression and gene expression. Lamin B1 associates with PCNA (proliferating cell nuclear antigen) to control DNA replication (41) and binds Nup to control NPC incorporation in the NE (21); lamin A/C associates with and stabilizes Rb (retinoblastoma protein) and restrains the G 1 /S transition (15,43) (Fig. 3A).…”

Section: Pi3k␤ Expression Is Necessary For Ne Integritymentioning

confidence: 99%

Phosphoinositide 3-Kinase Beta Protects Nuclear Envelope Integrity by Controlling RCC1 Localization and Ran Activity

Redondo-Muñóz

Pérez-García

Rodriguez

et al. 2015

Molecular and Cellular Biology

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The nuclear envelope (NE) forms a barrier between the nucleus and the cytosol that preserves genomic integrity. The nuclear lamina and nuclear pore complexes (NPCs) are NE components that regulate nuclear events through interaction with other proteins and DNA. Defects in the nuclear lamina are associated with the development of laminopathies. As cells depleted of phosphoinositide 3-kinase beta (PI3K␤) showed an aberrant nuclear morphology, we studied the contribution of PI3K␤ to maintenance of NE integrity. pik3cb depletion reduced the nuclear membrane tension, triggered formation of areas of lipid bilayer/ lamina discontinuity, and impaired NPC assembly. We show that one mechanism for PI3K␤ regulation of NE/NPC integrity is its association with RCC1 (regulator of chromosome condensation 1), the activator of nuclear Ran GTPase. PI3K␤ controls RCC1 binding to chromatin and, in turn, Ran activation. These findings suggest that PI3K␤ regulates the nuclear envelope through upstream regulation of RCC1 and Ran. In eukaryotic cells, the nuclear envelope (NE) is a physical barrier that separates the genomic material from the cytosol; it regulates nucleocytoplasmic traffic and controls nuclear events. The NE is formed by two concentric lipid bilayers surrounding the chromatin, the outer nuclear membrane (ONM) and the inner nuclear membrane (INM). The latter is covered on the internal side by the nuclear lamina, which provides mechanical stability to the nucleus (1-4). Nuclear lamins (A and B types) are type V intermediate filaments that interact between themselves, with other proteins, and with DNA and act as structural elements and as regulators of DNA replication, repair, epigenetic modification, and chromatin organization (2-8). B-type lamins are expressed in most cell types and regulate DNA replication, gene expression, cell differentiation, and proliferation; lamin B defects are present in cancer (2-4, 9). The other nuclear lamina component is lamin A/C, whose mutations are responsible for premature aging disorders and aggressive tumor behavior (2-4, 10, 11). Nuclear lamina defects are associated with various diseases, termed laminopathies, which appear at a low incidence but are often life threatening. The premature aging phenotype of some laminopathies and the NE defects in cancer illustrate the cross talk between NE integrity and genomic stability (2-15).The NE is crossed by the nuclear pore complexes (NPCs) (16). Nuclear pores are channels composed of nucleoporins (Nups) that assemble into a donut structure that permits the nucleocytoplasmic traffic of macromolecules (16)(17)(18)(19)(20)(21)(22). Nups interact with lamins and NE proteins to regulate chromatin structure (21, 23). The dynamics of NPC formation link it to that of the NE in mitosis, but NPCs are also formed during interphase in an already formed NE (16)(17)(18)(19)(20)(21)(22). The small GTPase Ran regulates NE/NPC assembly (24-26). Ran is activated by the chromatin-bound form of RCC1 (regulator of chromosome condensation 1) (20). NE/ NPC assembly i...

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Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition

Cited by 65 publications

References 42 publications

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction

Phosphoinositide 3-Kinase Beta Protects Nuclear Envelope Integrity by Controlling RCC1 Localization and Ran Activity

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