Suppression of fibroblast cell growth by overexpression of LIM‐kinase 1

Higuchi, Osamu; Baeg, Gyeong-Hun; Akiyama, Tetsu; Mizuno, Kensaku

doi:10.1016/0014-5793(96)01072-1

Cited by 17 publications

(10 citation statements)

References 21 publications

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“…These findings are in concurrence with the idea that chromosomal abnormalities are intimately involved in generation of cell cycle defects, which frequently become a phenotypic characteristic of advanced cancers [38]. Although LIMK1 expression led to a transient arrest in G1/S phase it did not inhibit cell proliferation as evident from BrDU incorporation, which is in contrast to the earlier reports on the inhibitory effect of LIMK1 on NIH3T3 cell proliferation [39]. The transient nature of G1 arrest implies a temporary block that possibly depends on expression of one or more key proteins.…”

Section: Discussionsupporting

confidence: 87%

Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer

et al. 2007

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Background: LIM kinase 1 (LIMK1), a LIM domain containing serine/threonine kinase, modulates actin dynamics through inactivation of the actin depolymerizing protein cofilin. Recent studies have indicated an important role of LIMK1 in growth and invasion of prostate and breast cancer cells; however, the molecular mechanism whereby LIMK1 induces tumor progression is unknown. In this study, we investigated the effects of ectopic expression of LIMK1 on cellular morphology, cell cycle progression and expression profile of LIMK1 in prostate tumors.

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Section: Discussionsupporting

confidence: 87%

Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer

et al. 2007

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“…Our findings in GNB implicate that, by limiting the access of Id2 to the nuclear targets, expression of ENH may be a crucial safeguard against full-blown anaplasia in more differentiated tumors. As we have shown for ENH, other members of the PDZ-LIM domain family of proteins are more abundantly expressed in nontransformed cells and suppress growth of tumor cells (39)(40)(41). It is likely that this is a general attribute of this family of proteins.…”

Section: Discussionmentioning

confidence: 71%

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

Lasorella

Iavarone

2006

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

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Id2 is a natural inhibitor of the basic helix-loop-helix transcription factors and the retinoblastoma tumor suppressor protein. Active Id2 prevents differentiation and promotes cell-cycle progression and tumorigenesis in the nervous system. A key event that regulates Id2 activity during differentiation is translocation from the nucleus to the cytoplasm. Here we show that the actin-associated protein enigma homolog (ENH) is a cytoplasmic retention factor for Id2. ENH contains three LIM domains, which bind to the helixloop-helix domain of Id proteins in vitro and in vivo. ENH is up-regulated during neural differentiation, and its ectopic expression in neuroblastoma cells leads to translocation of Id2 from the nucleus to the cytoplasm, with consequent inactivation of transcriptional and cell-cycle-promoting functions of Id2. Conversely, silencing of ENH by RNA interference prevents cytoplasmic relocation of Id2 in neuroblastoma cells differentiated with retinoic acid. Finally, the differentiated neural crest-derived tumor ganglioneuroblastoma coexpresses Id2 and ENH in the cytoplasm of ganglionic cells. These data indicate that ENH contributes to differentiation of the nervous system through cytoplasmic sequestration of Id2. They also suggest that ENH is a restraining factor of the oncogenic activity of Id proteins in neural tumors.differentiation ͉ enigma homolog ͉ Id proteins ͉ neural cancer I d2 is one of the four members of the Id protein family, a group of proteins known as inhibitor of differentiation (1, 2). Id2 lies at the center of a molecular network including the retinoblastoma (Rb) tumor suppressor protein and the basic helix-loop-helix (bHLH) transcription factors, the best-known targets for inhibition by Id2 (3, 4). These connections probably operate in a variety of cell types, but our work has characterized them in the nervous system (5-7). In this tissue, overexpression of Id proteins inhibits differentiation whereas ablation of Id genes induces premature differentiation of various neural cell types in vitro and in vivo (8-10). As physiologic regulator of Id2, Rb cooperates with bHLH transcription factors to promote cell-cycle arrest and differentiation in the developing brain. This pathway is subverted in tumor cells. Malignant transformation in the central and peripheral nervous system coincides with frequent elevation of Id2, a process typically implemented by the activation of oncoproteins such as Myc and Ews-Fli1 that up-regulate Id2 gene transcription, (6,7,11,12). The aberrant accumulation of Id2 contributes to uncontrolled proliferation and neoangiogenesis, two hallmarks of neural cancer (13).There is general agreement with the notion that differentiation of a variety of cell types requires elimination of Id function. However, the mechanisms by which the signaling pathways initiating differentiation in the nervous system inactivate Id proteins are unknown. Although Id are viewed mainly as nuclear proteins, recent papers reported that relocation of Id proteins to the cytoplasm is an effective...

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“…LIMK1 seems to act as a negative regulator of cell growth and appears to play a role in tumor suppression (17). In man, LIMK1 is found predominantly in the brain, and the hemizygous deletion of the 7q11.23 region containing LIMK1 has been implicated in the visuospatial constructive cognition defect of Williams syndrome (18,19).…”

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confidence: 99%

LIM Kinase 1 Activates cAMP-responsive Element-binding Protein during the Neuronal Differentiation of Immortalized Hippocampal Progenitor Cells

Yang

Yoon

Min

et al. 2004

Journal of Biological Chemistry

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LIM kinase 1 (LIMK1), a novel member of a subclass of the protein-serine/threonine kinases, is known to play a role in the development and maintenance of neuronal circuits that mediate cognitive function. Genetic studies have implicated a mutation of LIMK1 as a causative factor in the impairment of visuospatial cognition in a neurodevelopmental disorder, Williams syndrome. A transcriptional factor, cAMP-responsive element-binding protein (CREB), is thought to be involved in the formation of many types of synaptic plasticity involving learning and memory. In the present study we show that the LIMK1 activity is markedly induced during the differentiation of immortalized hippocampal progenitor (H19-7) cells. We found that the addition of neurogenic growth factor to H19-7 cells induces specific binding between LIMK1 and active CREB, that LIMK1 directly phosphorylates CREB, and that this leads to the stimulation of subsequent cAMP-responsive element-mediated gene transcription during H19-7 cell neuronal differentiation. In addition, we also found that LIMK1 activation occurs through Rac/Cdc42-and p21-activated kinase-mediated signaling pathways. Moreover, when the plasmid encoding kinase-inactive LIMK1 was transfected to block the activation of endogenous LIMK1, the neuronal differentiation of H19-7 cells was significantly suppressed. These findings suggest that LIMK1 activation and subsequent CREB phosphorylation are important in the neuronal differentiation of central nervous system hippocampal progenitor cells.Trophic factors as well as growth factors, which both act by binding to cell surface receptors, are essential for the development of the vertebrate nervous system (1, 2). Trophic factors induce the phosphorylation of their receptor tyrosine kinases, which promote a variety of downstream intracellular signaling pathways and ultimately yield marked changes, and exert long lasting effects, such as those associated with promoting cell growth, survival or death, and proliferation or differentiation. The activation of cellular signaling cascades by growth factors involves the phosphorylation of transcription factors and leads to changes in the expressions of terminal differentiation genes in postmitotic neurons and results in alterations of the neuron mature phenotype. Therefore, transcription factors in neural progenitor cells are important in the establishment of neuronal cell identity.cAMP-responsive element (CRE) 1 -binding protein (CREB) is a central transcription factor that mediates cAMP-responsive genes by binding as a dimer to a conserved CRE motif (3). The CREB plays an important role in cell survival and differentiation by a variety of growth factors (4, 5). Numerous signaling pathways are known to activate CREB, including protein kinase C (6), Ca 2ϩ /calmodulin-dependent protein kinases (7, 8), Ras-dependent p105 kinase (9), p90rsk (10), and Rsk2 (11). In rodents, studies support a role for CREB in learning, memory, and synaptic plasticity (12, 13). The functional specificities of CREB in neuronal deve...

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Suppression of fibroblast cell growth by overexpression of LIM‐kinase 1

Cited by 17 publications

References 21 publications

Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer

Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

LIM Kinase 1 Activates cAMP-responsive Element-binding Protein during the Neuronal Differentiation of Immortalized Hippocampal Progenitor Cells

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