The nuclear lamina and its proposed roles in tumorigenesis: Projection on the hematologic malignancies and future targeted therapy

Prokocimer, Miron; Margalit, Ayelet; Gruenbaum, Yosef

doi:10.1016/j.jsb.2006.02.016

Cited by 64 publications

(63 citation statements)

References 89 publications

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“…Cancer cells also often exhibit changes in lamin A expression and nuclear morphology that resemble the phenotype observed in laminopathies, indicating that cancer cells may experience transient nuclear envelope rupturing (62,63). This was shown experimentally; cancer cells forced to squeeze through tiny pores undergo repeated rupturing and repair of the nuclear envelope (64,65), further indicating that the nuclear stress response is relevant to migrating cells, possibly contributing to metastasis.…”

Section: Discussionmentioning

confidence: 89%

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Micco

Frera

Lugrin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

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Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavirmediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity.inflammasome | nuclear envelope stress | DNA sensors | zmpste24 | Nelfinavir

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Section: Discussionmentioning

confidence: 89%

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Micco

Frera

Lugrin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

113

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“…Because progerin does not share this function, delayed senescence would not be apparent. Increasing evidence suggests that A-type lamins act as tumor suppressors in part due to their regulation of the pRB pathway (Prokocimer et al, 2006;Dorner et al, 2007). Strikingly, an osteosarcoma (often associated with pRB inactivation in humans; Wadayama et al, 1994) was recently detected in an HGPS patient (King et al, 1978;Shalev et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Kudlow

Stanfel

Burtner

et al. 2008

MBoC

115

118

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare, debilitating disease with early mortality and rapid onset of aging-associated pathologies. It is linked to mutations in LMNA, which encodes A-type nuclear lamins. The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation. The cellular consequences of progerin expression underlying the HGPS phenotype remain poorly understood. Here, we stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblasts to compare the effects of different mutants on nuclear morphology and cell proliferation. We find that expression of progerin leads to inhibition of proliferation in a high percentage of cells and slightly premature senescence in the population. Expression of a stably farnesylated mutant of lamin A phenocopied the immediate proliferative defects but did not result in premature senescence. Either p53 inhibition or, more surprisingly, expression of the catalytic subunit of telomerase (hTERT) suppressed the early proliferative defects associated with progerin expression. These findings lead us to propose that progerin may interfere with telomere structure or metabolism in a manner suppressible by increased telomerase levels and possibly link mechanisms leading to progeroid phenotypes to those of cell immortalization. INTRODUCTIONThe nuclear lamins are broadly expressed and constitute the only intermediate filament proteins localized to the nucleus (Smith et al., 2005;Bridger et al., 2007;Dechat et al., 2008). Given the ability of lamins to form stable polymers resulting from coiled-coil interactions, they have typically been ascribed a structural role in the nucleus (McKeon et al., 1986;Lammerding et al., 2004Lammerding et al., , 2006; however, a variety of regulatory roles have also been proposed (Spann et al., 1997;Spann et al., 2002;Frock et al., 2006;Ivorra et al., 2006;Nitta et al., 2006Nitta et al., , 2007Scaffidi and Misteli, 2008). The two classes of lamins, B-type and A-type (of which lamin A and lamin C are the most prominent), have different patterns of expression. Whereas, isoforms of lamin B are expressed in all cells throughout development, lamins A and C (lamin A/C) are not expressed early in development. Instead, their expression begins during midgestation and is most prominent in differentiating and terminally differentiated cells (Rober et al., 1989).Mutations in LMNA (encoding all A-type lamins) are associated with at least 12 different human genetic disorders (Kudlow et al., 2007). Of these, at least three have features reminiscent of premature aging. The most common LMNAassociated premature aging-like syndrome, Hutchinson-Gilford progeria syndrome (HGPS), is often caused by a single nucleotide change in exon 11 of the LMNA gene (Cao and Hegele, 2003;De Sandre-Giovannoli et al., 2003;Eriksson et al., 2003). This mutation, generally referred to as G608G, is silent with regard to the coded a...

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“…Clearly, this negative correlation is not absolute; many cell types have both LBR and lamin A/C co-existing within the same nuclear envelope. Furthermore, confined to hematologic cell types (normal and malignant), the published literature is confusing with regards to amounts of lamin A/C (see a recent comprehensive review [44]). Even so, present studies from our laboratory and our earlier results with HL-60 cells, [16] stimulate some speculative thoughts.…”

Section: Discussionmentioning

confidence: 99%

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

Zwerger

Herrmann

Gaines

et al. 2008

Experimental Hematology

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Objective-Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane. Recent studies have demonstrated that genetic deficiency of LBR during granulopoiesis results in hypolobulation of the mature neutrophil nucleus, as observed in human Pelger-Huët anomaly (PHA) and mouse ichthyosis (ic). In this study we have utilized differentiated promyelocytes (EPRO cells) that were derived from the bone marrow of homozygous and heterozygous ichthyosis mice to examine changes to the expression of nuclear envelope proteins and heterochromatin structure that result from deficient LBR expression.Materials and Methods-Wildtype (+/+), heterozygous (+/ic) and homozygous (ic/ic) granulocytic forms of EPRO cells were analyzed for the expression of multiple lamins and inner nuclear envelope proteins by immunostaining and immunoblotting techniques. The heterochromatin architecture was also examined by immunostaining for histone lysine methylation.Results-Wildtype (+/+) and heterozygous (+/ic) granulocytic forms revealed ring-shaped nuclei and contained LBR within the nuclear envelope; ic/ic granulocytes exhibited smaller ovoid nuclei devoid of LBR. The pericentric heterochromatin of undifferentiated and granulocytic ic/ic cells was condensed into larger spots and shifted away from the nuclear envelope, compared to +/+ and +/ic cell forms. Lamin A/C, which is normally not present in mature granulocytes, was significantly elevated in LBR-deficient EPRO cells.Conclusions-Our observations suggest roles for LBR during granulopoiesis which may involve augmenting nuclear membrane growth, facilitating compartmentalization of heterochromatin and promoting down-regulation of lamin A/C expression. Category Granulopoiesis

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The nuclear lamina and its proposed roles in tumorigenesis: Projection on the hematologic malignancies and future targeted therapy

Cited by 64 publications

References 89 publications

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Granulocytic nuclear differentiation of lamin B receptor–deficient mouse EPRO cells

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