Cytoskeletal changes in cell transformation and tumorigenesis

Pawlak, Geraldine; Helfman, David M.

doi:10.1016/s0959-437x(00)00154-4

Cited by 288 publications

(254 citation statements)

References 75 publications

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“…This exclusion from stabilized contact sites and the reduced spreading suggest that Ndr2 may negatively regulate substrate adhesion in differentiated PC12 cells, possibly by reducing the stability of actin-dependent contact sites. Reduced PC12 cell adhesion, by virtue of a reduced contact inhibition, may also explain the increased proliferation of these cells (20) in line with the observation that inhibition of the potential Ndr-kinase activator S100B (21) both induces flattening of glia cells and reduces their proliferation (22). Some S100 proteins are also potent inducers of neurite outgrowth (23).…”

Section: Discussionmentioning

confidence: 55%

Neuronal Functions of the Novel Serine/Threonine Kinase Ndr2

Stork

Zhdanov

Kudersky

et al. 2004

Journal of Biological Chemistry

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We have identified a novel member of the Ndr subfamily of serine/threonine protein kinases, Ndr2, as a gene product that is induced in the mouse amygdala during fear memory consolidation and examined a possible function of this kinase in neural differentiation. Expression of Ndr2 mRNA was detected in various cortical and subcortical brain regions, as well as non-neuronal tissues. Its expression in the amygdala was increased 6 h after Pavlovian fear conditioning training and returned to control levels within 24 h. To study intracellular localization and functions of Ndr2, EGFP::Ndr2 fusion proteins were expressed in rat pheochromocytoma (PC12) cells and acutely isolated cortical neurons, thereby revealing an association of Ndr2 with the actin cytoskeleton in somata, neurites and filopodia, in spines and at sites of cell contact. Co-precipitation and pulldown experiments support this finding. Evidence for an involvement of Ndr2 in actin-mediated cellular functions further comes from the observation of decreased cell spreading and changes in neurite outgrowth that were associated with protein serine phosphorylation in transfected PC12 cells. Together, our data suggest that Ndr2 is an interesting candidate gene for the regulation of structural processes in differentiating and mature neuronal cells.Stimulus-dependent modifications of cell structure and connectivity in the central nervous system are basic elements of long term memory formation. Protein kinases and protein phosphatases are key regulators of these processes, which they control and co-ordinate through the phosphorylation and/or dephosphorylation of neurotransmitter receptors and ion channels, cytoskeleton elements, cell surface molecules, and transcription factors (1).We have employed a classic fear conditioning paradigm to isolate candidate genes involved in memory-related functions in the brain (2). Fear conditioning is highly amenable to cellular and molecular approaches to learning and memory, because conditioned subjects (a) very quickly learn to associate a previously neutral sensory stimulus (conditional stimulus) and an aversive, unconditional stimulus during fear conditioning training and (b) develop a robust and easily measurable long term memory after a single training session. Moreover, the neuronal circuits and cellular mechanisms that underlie classic fear conditioning have been investigated in detail (reviewed in Ref.3). These conceptual and technical advantages have allowed researchers to show that, among other factors, protein kinase A, mitogen-activated protein kinase and calcium/calmodulin-dependent kinases are critical for fear conditioning (summarized in Ref. 4). Some of these protein kinase activities could even be tracked down to the amygdala (5-7). Recent evidence further suggests an involvement of Rho-mediated signaling pathways and the Rho-associated kinase (p160 ROCK ) in amygdala plasticity after fear conditioning (8). This pathway may be of particular importance, because it controls actinmediated changes in dendrite and spine...

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Section: Discussionmentioning

confidence: 55%

Neuronal Functions of the Novel Serine/Threonine Kinase Ndr2

Stork

Zhdanov

Kudersky

et al. 2004

Journal of Biological Chemistry

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“…Besides adhesion and migration (Lauffenburger and Horwitz, 1996;Pawlak and Helfman, 2001), it is also influenced by increased proliferative effects. For this reason, we additionally investigated this inherent feature of tumor cells (Hanahan and Weinberg, 2000).…”

Section: Discussionmentioning

confidence: 99%

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

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Tumorigenesis and tumor progression are associated with dysfunction of the nuclear transport machinery at the level of import and export receptors (karyopherins). Recent studies have shown that the nuclear import factor karyopherin-a2 (KPNA2) is a novel prognostic marker for poor prognosis in human breast cancer. Based on the well-defined hallmarks of cancer progression, we performed a detailed in vitro characterization of the phenotypic effects caused by KPNA2 overexpression and KPNA2 silencing in benign and malignant human breast cells. KPNA2 overexpression clearly increased proliferation of MCF7 tumor cells and further led to a reduction of cell-matrix adhesion in benign MCF10A cells, whereas cell migration was significantly increased (Po0.0001) in both tumor models. Remarkably, these individual effects of KPNA2 overexpression on proliferation, cell-matrix adhesion and migration resulted in an increased colony spreading of benign MCF10A breast cells and malignant MCF7 tumor cells (Po0.001), which is a hallmark of cancer progression. Conversely, RNA interference-mediated KPNA2 silencing caused a complete inhibition of MCF7 tumor cell proliferation and migration (Po0.0001). In addition, in these experiments apoptosis was increased (Po0.05) and formation of tumor cell colonies was reduced (Po0.01). Thus, KPNA2 overexpression provoked increased aggressiveness of malignant MCF7 breast tumor cells and induced a shift in benign MCF10A breast cells toward a malignant breast cancer phenotype. In conclusion, we demonstrate for the first time in experimental tumor models that forced KPNA2 expression drives malignant features relevant for breast cancer progression, while its silencing is required for the remission of those progressive phenotypes. This study gives clear evidence that KPNA2 acts as a novel oncogenic factor in human breast cancer, in vitro.

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“…Second, disruption of actin filaments is a known feature following oncogene-induced cell transformation (Pawlak and Helfman, 2001). Clearly, literature has documented evidence of elevated expression of thymosin b4 (a G-actin-sequestering protein that inhibits actin polymerisation) and loss of tropomyosin (an F-actin-stabilizing protein) correlating with increased aggressiveness of carcinoma cells (Franzen et al, 1996;Kobayashi et al, 2002;Wang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Changes in actin cytoskeleton in malignant cells have been found to be correlated with altered expression of various ABPs (Vandekerckhove et al, 1990;Button et al, 1995;Wang et al, 1996;Clark et al, 2000;Pawlak and Helfman, 2001). Experimental manipulations restoring the normal expression levels of several different types of ABPs have been successful in suppressing the phenotype of transformed cells (Gluck et al, 1993;Tanaka et al, 1995;Nikolopoulos et al, 2000), therefore implying that deregulation of ABPs directly contribute to oncogene-induced transformed phenotype of tumour cells.…”

mentioning

confidence: 99%

Profilin-1 is a negative regulator of mammary carcinoma aggressiveness

et al. 2007

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Expression of profilin-1 (Pfn1) is downregulated in breast cancer cells, the functional significance of which is yet to be understood. To address this question, in this study we evaluated how perturbing Pfn1 affects motility and invasion of breast cancer cells. We show that loss of Pfn1 expression leads to enhanced motility and matrigel invasiveness of MDA-MB-231 breast cancer cells. Interestingly, silencing Pfn1 expression is associated with downregulation of both cell -cell and cell -matrix adhesions with concomitant increase in motility and dramatic scattering of normal human mammary epithelial cells. Thus, these data for the first time suggest that loss of Pfn1 expression may have significance in breast cancer progression. Consistent with these findings, even a moderate overexpression of Pfn1 induces actin stress-fibres, upregulates focal adhesion, and dramatically inhibits motility and matrigel invasiveness of MDA-MB-231 cells. Using mutants of Pfn1 that are defective in binding to either actin or proline-rich ligands, we further show that overexpressed Pfn1 must have a functional actin-binding site to suppress cell motility. Finally, animal experiments reveal that overexpression of Pfn1 suppresses orthotopic tumorigenicity and micro-metastasis of MDA-MB-231 cells in nude mice. These data imply that perturbing Pfn1 could be a good molecular strategy to limit the aggressiveness of breast cancer cells.

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Cytoskeletal changes in cell transformation and tumorigenesis

Cited by 288 publications

References 75 publications

Neuronal Functions of the Novel Serine/Threonine Kinase Ndr2

Neuronal Functions of the Novel Serine/Threonine Kinase Ndr2

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

Profilin-1 is a negative regulator of mammary carcinoma aggressiveness

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