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Lamin polymerization: a regulatory process for programmed cell survival.


During early phases of cell division, nuclear identity is lost and regained towards the end of the cell cycle, i.e. the telophase. Disappearance and reappearance of the nuclear envelope (NE) during cell cycle is controlled by intermediate filament phosphoprotein called lamin. Lamins are an integral part of the nuclear matrix and are apposed to the inner nuclear membrane [7]. For this dynamic behavior of NE many explanations have been proposed by various workers, however; no precise mechanism has been unified so far. Any mishap during this long and complicated, yet not well understood process of lamin polymerization can become the root cause of cellular pathogenesis [17].

A group of cellular enzymes enter the interphase nucleus and are most likely responsible for the cell cycle events. Protein phosphatase 1 (PP1), a Ser/Thr phosphatase, is the key enzyme responsible for dephosphorylation of lamins in the cell nucleus.

Dephosphorylation of lamins is essential at the right event in the normal direction [21]. Any deregulation in this phosphorylation-dependent polymerization process may lead to pathogenesis[see review 20].

Programmed cell death (PCD)

In multi-cellular organisms, cells are eliminated from the body in a well defined genetically programmed manner called programmed cell death (PCD). PCD is a precise physiological mechanism important for removal of unwanted cells from a population of healthy cells by activation of an intrinsic suicide program without evoking an inflammatory response in the body [15]. It also plays an important role in development and maintenance of homeostasis in adult tissues. PCD is accomplished not only by the process of apoptosis (as is generally considered), but also by terminal differentiation. These two cell elimination systems share some common pathways but on the whole they are quite distinct [16]. In apoptosis, death inducing factors induce the release of cytochrome-C from the mitochondria, which in turn activates procaspase-9, finally resulting in procaspase-3 cleavage. Once active, caspase-3 induces all the characteristic events of apoptosis [13]. Early morphological events of apoptosis include disarray of actin cytoskeleton at the adhesion sites resulting in loosening of cell to cell contacts [10]. This is followed by cell shrinkage, chromatin condensation, internucleosomal DNA fragmentation, formation of apoptotic bodies and their removal by phagocytosis [16,26]. In terminal differentiation, both markers of apoptosis, i.e., the characteristic DNA ladder formation by DNaseI and down regulation of bcl-2 expression, are absent [16]. Terminal differentiation is characterized by degree of expression of bcl-2, elimination of cell organelles such as nucleus and activation of mitochondrial membrane-bound transglutaminase [15,24].

Regulators of PCD

Bcl-2 family of proteins is a well established apoptotic regulator, which controls the permeability of outer mitochondrial membrane. Some of the members of this family are pro-apoptotic (Bad, Bid, Bik) while some are antiapoptotic (Bcl-2, BclXL) [18]. p53 has been called the master regulator of apoptosis, as it regulates apoptosis by two different mechanisms. First, it acts as a transcriptional factor to regulate expression of many genes involved in apoptosis. Second, it can activate Bax in mitochondria to antagonize the antiapoptotic ability of Bcl-2 and Bcl-XL [9]. Earlier, it has been reported that starvation and steroid hormones also act as apoptotic modulators [11,15]. Starvation down regulates apoptosis, whereas, steroid hormones influence PCD in a tissue specific manner. The same hormone can inhibit PCD in one tissue and may promote it in another tissue [15].


Nucleoskeleton, analogous to the cytoskeleton in the cytoplasm, is crucial for maintaining the shape of interphase nucleus. It is mainly composed of nuclear lamina, which at the periphery, interacts with the inner nuclear membrane and is interconnected with cytoskeleton at the pore complex. It consists mainly of intermediate filaments called lamins and microfilaments cal led act ins and DNA topoisomeraseII (Fig.1). All these together form a tripartite network in the nucleoplasm and provide topological surfaces for complex processes of DNA replication and RNA transcription and processing of RNA [19].


Lamins are cytoskeletal proteins belonging to the family of intermediate filaments. They are the major components of a filamentous network underlying the inner nuclear membrane, termed as the nuclear lamina. Nuclear membrane, along with nuclear lamina on its inner periphery, constitutes the nuclear envelope (NE). Nuclear lamina plays an essential role in maintaining the integrity of the NE and it provides anchoring sites for chromatin [7,5].

Lamins are of two types, lamin B (B1 and B2) which is present in all somatic cells and lamin A (A and C) expressed only in differentiated cells. Lamins A and C are splice variants of a single lamin A (LMNA) gene, whereas lamins B1 and B2 are encoded by two separate LMNB1 and LMNB2 genes. The major components of nuclear lamina are lamins B and A [8,14].

Lamins, have long been known for their role in nuclear architecture, however, recently they have been proved to play a crucial role in cell survival also. During mitosis, the NE remains disintegrated to enable the association of condensed chromosomes with mitotic spindles. While by the end of mitosis, in telophase, dispersed lamins again reassemble to reform the NE thereby enclosing the decondensing chromosomes inside. However, if lamins fail to reassemble at this crucial stage in cell cycle, the cell is sentenced to undergo programmed cell death [22].

Mechanism of lamin polymerization during cell cycle

At the onset of mitosis, NE disintegrates and throughout the mitosis the disrupted nuclear membrane along with lamin B remains dispersed in cytoplasm in the form of small vesicles[19]. In telophase, again the ER derived membrane associates with chromatin to reform the NE. Reassembly of lamin B depends on protein phosphatase-1 (PP1) mediated dephosphorylation and disintegration depends on phosphorylation by lamin kinases.

At telophase stage, PP1 (a Ser/Thr phosphatase) is targeted to lamin B by A-kinase anchoring protein (AKAP149) which is a membrane bound PP1 binding protein (Fig.2(c)). PP1 then dephosphorylates lamin B and promotes its polymerization into the assembling NE during G1 phase (Fig.2 (d)). However, at G1/S transition, phosphorylation of NE associated AKAP149 by PKA causes release of PP1 from the AKAP149 complex resulting in downregulation of PP1 activity towards assembled lamins (Fig.2(a)). In spite of this, lamin B remains hypophosphorylated till the onset of next mitosis. Steen et al. [21] suggested that this may happen because by this time lamin B kinases are also down regulated. They are activated only at the beginning of mitosis, causing phosphorylation mediated depolymerization of nuclear lamina (Fig.2(b)). Moreover the new laminB synthesized de novo in S phase are not phosphorylated and therefore do not require a dephosphorylation step for polymerization. Consequently, the lamin B phosphatase activity of PP1, mediated by NE associated AKAP149, appears to be dispensable beyond the G1/S transition till the next telophase sets in [21]. However, the consequences of PP1 inhibition from telophase till G1/S transition can be fatal for the cell.

Lamins as regulators of PCD

Apoptosis and terminal differentiation are the two subsets of PCD. Lamin degradation is one of the features of apoptosis. However studies have shown that they even play a role in the induction of apoptosis. Role of lamins in cell elimination via terminal differentiation has not been worked out so far and it is proposed in the present work.


Steel and Collas[22] have shown that lamin B are a prerequisite for cell survival. As already explained, under normal conditions PP1 is targeted to NE by AKAP149 at the end of mitosis and it induces lamin B assembly. However, if PP1 targeting to NE is inhibited, lamin B assembly is abolished and lamin B is degraded in a caspase dependent fashion. This is followed by nuclear fragmentation indicating that apoptosis mechanism has set in.

However, at the same time lamin A/C assembly remains unaffected and NE forms even in AKAP147 deficient cells, indicating that only lamin B required AKAP149-mediated concentration of PP1 for the nuclear membrane assembly [22,1]. Possible reason for this, as suggested by Steen and Collas, could lie in the distinct assembly pathways of lamin A/C and B. At mitosis, lamin A/C are more soluble than lamin B (which remain mostly membrane bound), and thus may not require spatially restricted, elevated concentration of phosphatase activity to be dephosphorylated and polymerized.

Studies have shown that lamin B concentrate on the chromosome surface in telophase, and lamin A is first found in an unpolymerized form in the nucleoplasm, before it gets polymerised into the lamina [12,5]. However under in-vitro conditions if mitotic chromosomes are kept in contact with unpolymerised lamin A/C, some elements on chromosome surface induce polymerization in lamin A and C to form a coat on the surface of chromosomes [4]. This, along with the fact that PP1 is localized on chromosomes in anaphase [23], suggests that PP1 is responsible for polymerization of lamin A/C also, but some other PP1 targeting protein may be there which targets PP1 to lamin A/C and this targeting protein might be getting activated only after the major components of NE including the pore complex have assembled again.

In the KE37 lymphoid cells, which normally do not express lamin A/C, failure of lamin B assembly even induces the expression of lamin A genes. It is as if cell is trying to adopt a rescue mechanism to compensate for the absence of lamin B [22,1]. To explain this phenomenon Steen and Collas have suggested the presence of a signaling mechanism that derepresses the LMNA gene in response to a mislocalization of lamin B at the end of mitosis. The interaction of lamins and lamin-binding proteins with transcriptional activators (8, 2) further supports their hypothesis.

Regardless of the nuclear assembly of lamins A/C, lamin B-deficient cells still undergo apoptosis, indicating that NE targeting of lamin B is sine qua non for cell survival. However, presence of some additional PP1 dependent apoptosis inducing mechanism, unrelated to lamin assembly, can not be ruled out [22].

Terminal differentiation

Terminal differentiation is a form of PCD mainly characterized by the process of enucleation, the minor changes such as Bcl 2 expression does not alter and cell does not become round, probably no transformation of F actin to G actin [16].

Certain reported facts about the properties and role of lamins suggest that lamins might be playing a crucial role in PCD via terminal differentiation. The expression of lamin A/C is restricted to differentiated cells only. Based on this, their role in maintenance of cell phenotype and differentiation has already been suggested [3]. Various authors have suggested their role in regulation of gene expression also, since lamins are known to interact with the key players of transcription mechanism, transcriptional activators and RNA polymerase II [8,2]. From this it can be inferred that specialized expression of lamin A/C in terminally differentiating cells might be regulating gene expression in such a manner that cell division almost ceases and the cell is directed on the track of subset of PCD, terminal differentiation. The characteristics of a cell undergoing terminal differentiation further support this hypothesis. In most of the terminally differentiating cells phenomena of enucleation is observed [15]. And lamins are known for their role in maintaining nuclear integrity, being an intergral part of nucleoskeleton and NE [19,7]. These arguments indicate that somehow disappearance of nucleus in terminal differentiation might be related to the lamin gene expression. There are strong data to substantiate the hypothesis that lamins might be involved in terminal differentiation via regulating expression of genes involved in this process, including their own gene expression.


Deregulation of lamin polymerization may lead to pathogenesis via PCD It has been discussed already that lamin B deficient cells undergo untimely death via apoptosis [22] or as proposed via terminal differentiation. Though both the processes normally do not lead to pathogenesis, any mutational activity in lamins can certainly lead pathogenesis. If excessive apoptosis takes place under such conditions, it can give rise to various disorders such as ischemic diseases and neurodegenerative disorders [6].

We have hypothesized the role of lamins in terminal differentiation and any process impairing the normal path of terminal differentiation directly leads to cancer as cancer cells are basically the dedifferentiated form of normal cells. Therefore any deregulation of lamins during the process of terminal differentiation may result in cancer development. In addition to this, malfunctioning of nuclear lamina may give rise to muscular and lipodystrophies [25].


Lamins are playing a crucial role in the assembly of nucleoskeleton and NE and as regulators of PCD. They are acting as a deciding factor for cell survival. All these functions of lamins are dependent on the state of lamin phosphorylation. The key enzyme therefore in this whole process is a protein phosphatase, PP1. Absence of PP1 control for lamin polymerization can cause to cell death via apoptosis. Role of lamins in the PCD by means of terminal differentiation has also been proposed by in this review. Nevertheless, many questions still remain unanswered about lamins and their role in PCD, and need further research. How lamins regulate the process of terminal differentiation? How is apoptosis induced when lamin B are not targeted to NE at the end of mitosis? With newer functions of lamins coming to light and deeper study of PCD mechanisms, these questions will hopefully be answered in near future.




[1.] Burke, B. Lamins and apoptosis, 2001. A two-way street? J. Cell Biol., 153: F5-F7.

[2.] Cohen, M. Y. Gruenbaum, K.K. Lee and K.L. Wilson, 2001. Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina. Trends Biochem. Sci., 26: 41-47.

[3.] Constantinescu, D., H.L. Gray, P.J. Sammak, P. Gerald, G.P. Schatten and A.B. Csoka, 2006. Lamin A/C expression is a marker of mouse and human embryonic stem cell differentiation. Stem Cells, 24: 177-185.

[4.] Glass, J.R. and L. Gerace, 1990. Lamins A and C bind and assemble at the surface of mitotic chromosomes. J. Cell Biol., 111: 1047-1057.

[5.] Goldman, A.E., R.D. Moir, M. Montag-Lowy, M. Stewart and R.D. Goldman, 1992. Pathway of incorporation of microinjected lamin A into the nuclear envelope. J. Cell Biol., 119: 725-735.

[6.] Gupta, P.D. and S. Singh, 1997. Apoptosis in therapeutics. In Proceedings of the Symposium: Pathology of the Cell, Institute of Basic Medical Sciences, Chennai, pp-30-35.

[7.] Hozak, P., A.M.J. Sasseville, Y. Raymond and P.R. Cook, 1995. Lamin proteins form an internal nucleoskeleton as well as a peripheral lamina in human cells. J. Cell Sci., 108:635-644.

[8.] Kumaran, R.I., B. Muralikrishna and V.K. Parnaik, 2002. Lamin A/C speckles mediate spatial organization of splicing factor compartments and RNA polymerase II transcription. J. Cell Biol., 159: 783-793.

[9.] Li, D.W.C., J.P. Liu, P.C. Schmid, R. Schlosser, H. Feng, W.B. Liu, W. Yan, L. Gong, S.M. Sun, M. Deng, Y. Liu, 2006. Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15and Ser-37 to modulate its transcriptional and apoptotic activities. Oncogene., 25: 3006-3022.

[10.] Luciano, L., S. Groos, K.S. Rao, P.D. Gupta, and E. Raele, 1997. Early morphological events during apoptotic process in enterocytes. In Recent Advances in Microscopy of Cells, Tissues and Organs. Editor: P.M. Motta. pp: 391-395.

[11.] Luciano, L., P.D. Gupta, S. Groos and J. Adamski, 1995. Modulation of apoptosis by starvation: morphological and biochemical study of rat intestinal mucosa. Cell Death Differen., 2: 259-266.

[12.] Moir, R.D., M. Yoon, S. Khuon and R.D. Goldman, 2000. Nuclear lamins A and B1: Different pathways of assembly during nuclear envelope formation in living cells. J. Cell Biol., 151: 1155-1168.

[13.] Mukerjee, N., K.M. McGinnis, M.E. Gnegy, K.K. Wang,, Caspase mediated calcineurin activation contributes to IL-2 release during T cell activation. 2001. Biochem. Biophys. Res. Commun., 285: 1192-1199.

[14.] Parnaik, V.K., V.S. Jonnalagadda and Q.A. Hamid, 1994. Towards understanding lamin gene regulation. J. Biosci., 19: 615-628.

[15.] Pushkala, K. and P.D. Gupta, 2001. Steroid hormones regulate programmed cell death. Cytobios., 106: 201-217.

[16.] Rao, S.K., S. Zanotti, A.G. Reddy, F. Rauch, H.G. Mannherz and P.D. Gupta, 1998. Oestradiol Regulated Programmed Cell Death in Rat Vagina: Terminal Differentiation or Apoptosis? Cell Biol. Intl., 22: 105-113.

[17.] Robbins, E. and N.K. Gonatas, 1964. The ultrastructure of a mammalian cell during the mitotic cycle. J. Cell Biol., 21:429-463.

[18.] Ruvolo, P.P., X. Deng, W.S. May, 200. Phosphorylation of Bcl-2 and regulation of apoptosis. Leukemia., 15: 515-522.

[19.] Singh, S., J.R. Koke, P.D. Gupta and S.K. Malhotra, 1994. Multiple roles of intermediate filaments. Cytobios., 77: 41-57.

[20.] Singh, S. and P.D. Gupta, 1999. Deregulation of intermediate filament protein phosphorylation leads to pathogenesis: a review. Biomedical Letters, 59: 27-32.

[21.] Steen, R.L., M. Beullens, H.B. Landsverk, M. Bollen and P. Collas, 2003. AKAP149 is a novel PP1 specifier required to maintain nuclear envelope integrity in G1 phase. J. Cell Sci., 116: 2237-2246.

[22.] Steen, R.L. and P. Collas, 2001. Mistargeting of B-type lamins at the end of mitosis: implications on cell survival and regulation of lamins A/C expression. J. Cell Biol., 153:621-626.

[23.] Trinkle-Mulcahy, L., P.D. Andrews, S. Wickramasinghe, J. Sleeman, A. Prescott, Y.W. Lam, C. Lyon, J.R. Swedlow and A.I. Lamond, 2003. Time-lapse imaging reveals dynamic relocalization of PP1 throughout the mammalian cell cycle. Mol. Biol. Cell., 14: 107-117.

[24.] Vijayalakshmi, V. and P.D. Gupta, 1994. Estradiol-regulated transamidation of keratins by vaginal epithelial cell transglutaminase. Expl. Cell Res., 214: 358-66.

[25.] Wilson, K.L., 2000. The nuclear envelope, muscular dystrophy and gene expression. Trends Cell Biol., 10: 125-129.

[26.] Wyllie, A.H., 1980. Glucocorticoid induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature, 284: 555-556.

Gupta, P.D. and Saumyaa

Department of Biotechnology, Meerut Institute of Engineering and Technology (MIET), Meerut, U.P., India.

Corresponding Author: Dr. P.D. Gupta, Department of Biotechnology. Meerut Institute of Engineering and Technology (MIET), NH-58 by pass, Baghpat crossing, Meerut, 252-005, U.P., India E-mail:
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Title Annotation:Original Article
Author:Gupta, P.D.; Saumyaa
Publication:Advances in Medical and Dental Sciences
Article Type:Report
Geographic Code:9INDI
Date:May 1, 2008
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