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  1. Article ; Online: The fifth sense: Mechanosensory regulation of alpha-actinin-4 and its relevance for cancer metastasis.

    Thomas, Dustin G / Robinson, Douglas N

    Seminars in cell & developmental biology

    2017  Volume 71, Page(s) 68–74

    Abstract: Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the ... ...

    Abstract Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with α-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, α-actinin-4 exhibits a unique mechanosensory regulation that α-actinin-1 does not. This behavior is mediated, at least in part, by each protein's actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may provide major therapeutic targeting potential for cancer metastasis.
    MeSH term(s) Actinin/metabolism ; Animals ; Calcium/metabolism ; Humans ; Mechanotransduction, Cellular ; Neoplasm Metastasis ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Binding
    Chemical Substances ACTN4 protein, human ; Actinin (11003-00-2) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2017-06-01
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 1312473-0
    ISSN 1096-3634 ; 1084-9521
    ISSN (online) 1096-3634
    ISSN 1084-9521
    DOI 10.1016/j.semcdb.2017.05.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2918: Show issues Location:
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  2. Article ; Online: Myosin IIA Heavy Chain Phosphorylation Mediates Adhesion Maturation and Protrusion in Three Dimensions.

    Rai, Vandana / Thomas, Dustin G / Beach, Jordan R / Egelhoff, Thomas T

    The Journal of biological chemistry

    2017  Volume 292, Issue 8, Page(s) 3099–3111

    Abstract: Non-muscle myosin II (NMII) is a conserved force-producing cytoskeletal enzyme with important but poorly understood roles in cell migration. To investigate myosin heavy chain (MHC) phosphorylation roles in 3D migration, we expressed GFP-tagged NMIIA wild- ...

    Abstract Non-muscle myosin II (NMII) is a conserved force-producing cytoskeletal enzyme with important but poorly understood roles in cell migration. To investigate myosin heavy chain (MHC) phosphorylation roles in 3D migration, we expressed GFP-tagged NMIIA wild-type or mutant constructs in cells depleted of endogenous NMIIA protein. We find that individual mutation or double mutation of Ser-1916 or Ser-1943 to alanine potently blocks recruitment of GFP-NM-IIA filaments to leading edge protrusions in 2D, and this in turn blocks maturation of anterior focal adhesions. When placed in 3D collagen gels, cells expressing wild-type GFP MHC-IIA behave like parental cells, displaying robust and active formation and retraction of protrusions. However, cells depleted of NMIIA or cells expressing the mutant GFP MHC-IIA display severe defects in invasion and in stabilizing protrusions in 3D. These studies reveal an NMIIA-specific role in 3D invasion that requires competence for NMIIA phosphorylation at Ser-1916 and Ser-1943. In sum, these results demonstrate a critical and previously unrecognized role for NMIIA phosphorylation in 3D invasion.
    MeSH term(s) Animals ; COS Cells ; Cell Adhesion ; Cell Line ; Cell Line, Tumor ; Cell Movement ; Chlorocebus aethiops ; Humans ; Mice ; Myosin Heavy Chains/analysis ; Myosin Heavy Chains/metabolism ; Nonmuscle Myosin Type IIA/analysis ; Nonmuscle Myosin Type IIA/metabolism ; Phosphorylation
    Chemical Substances Nonmuscle Myosin Type IIA (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1)
    Language English
    Publishing date 2017-01-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M116.733402
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: 4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.

    Bryan, Darren S / Stack, Melinda / Krysztofiak, Katarzyna / Cichoń, Urszula / Thomas, Dustin G / Surcel, Alexandra / Schiffhauer, Eric S / Beckett, Michael A / Khodarev, Nikolai N / Xue, Lai / Poli, Elizabeth C / Pearson, Alexander T / Posner, Mitchell C / Robinson, Douglas N / Rock, Ronald S / Weichselbaum, Ralph R

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 117, Issue 36, Page(s) 22423–22429

    Abstract: Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and ...

    Abstract Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (
    MeSH term(s) Acetophenones/pharmacology ; Actins/metabolism ; Actomyosin/metabolism ; Animals ; Cell Adhesion/drug effects ; Cell Movement/drug effects ; Colorectal Neoplasms/metabolism ; Cytoskeleton/drug effects ; Cytoskeleton/metabolism ; Female ; HCT116 Cells ; Humans ; Mice ; Mice, Nude ; Neoplasm Metastasis/physiopathology
    Chemical Substances Acetophenones ; Actins ; Actomyosin (9013-26-7) ; 4-hydroxyacetophenone (G1L3HT4CMH)
    Language English
    Publishing date 2020-08-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2014639117
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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  4. Article ; Online: Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14.

    Surcel, Alexandra / Schiffhauer, Eric S / Thomas, Dustin G / Zhu, Qingfeng / DiNapoli, Kathleen T / Herbig, Maik / Otto, Oliver / West-Foyle, Hoku / Jacobi, Angela / Kräter, Martin / Plak, Katarzyna / Guck, Jochen / Jaffee, Elizabeth M / Iglesias, Pablo A / Anders, Robert A / Robinson, Douglas N

    Cancer research

    2019  Volume 79, Issue 18, Page(s) 4665–4678

    Abstract: Metastasis is complex, involving multiple genetic, epigenetic, biochemical, and physical changes in the cancer cell and its microenvironment. Cells with metastatic potential are often characterized by altered cellular contractility and deformability, ... ...

    Abstract Metastasis is complex, involving multiple genetic, epigenetic, biochemical, and physical changes in the cancer cell and its microenvironment. Cells with metastatic potential are often characterized by altered cellular contractility and deformability, lending them the flexibility to disseminate and navigate through different microenvironments. We demonstrate that mechanoresponsiveness is a hallmark of pancreatic cancer cells. Key mechanoresponsive proteins, those that accumulate in response to mechanical stress, specifically nonmuscle myosin IIA (MYH9) and IIC (MYH14), α-actinin 4, and filamin B, were highly expressed in pancreatic cancer as compared with healthy ductal epithelia. Their less responsive sister paralogs-myosin IIB (MYH10), α-actinin 1, and filamin A-had lower expression differential or disappeared with cancer progression. We demonstrate that proteins whose cellular contributions are often overlooked because of their low abundance can have profound impact on cell architecture, behavior, and mechanics. Here, the low abundant protein MYH14 promoted metastatic behavior and could be exploited with 4-hydroxyacetophenone (4-HAP), which increased MYH14 assembly, stiffening cells. As a result, 4-HAP decreased dissemination, induced cortical actin belts in spheroids, and slowed retrograde actin flow. 4-HAP also reduced liver metastases in human pancreatic cancer-bearing nude mice. Thus, increasing MYH14 assembly overwhelms the ability of cells to polarize and invade, suggesting targeting the mechanoresponsive proteins of the actin cytoskeleton as a new strategy to improve the survival of patients with pancreatic cancer. SIGNIFICANCE: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharmacologically targeted to inhibit the metastatic potential of pancreatic cancer cells.
    MeSH term(s) Acetophenones/pharmacology ; Actin Cytoskeleton ; Actinin/genetics ; Actinin/metabolism ; Animals ; Apoptosis ; Cell Proliferation ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/secondary ; Mice ; Mice, Nude ; Myosin Heavy Chains/genetics ; Myosin Heavy Chains/metabolism ; Myosin Type II/genetics ; Myosin Type II/metabolism ; Neoplasm Invasiveness ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Prognosis ; Tumor Cells, Cultured ; Tumor Microenvironment ; Xenograft Model Antitumor Assays
    Chemical Substances ACTN4 protein, human ; Acetophenones ; MYH14 protein, human ; Actinin (11003-00-2) ; Myosin Type II (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1) ; 4-hydroxyacetophenone (G1L3HT4CMH)
    Language English
    Publishing date 2019-07-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-18-3131
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.135/5: Show issues Location:
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  5. Article ; Online: Non-muscle myosin IIB is critical for nuclear translocation during 3D invasion.

    Thomas, Dustin G / Yenepalli, Aishwarya / Denais, Celine Marie / Rape, Andrew / Beach, Jordan R / Wang, Yu-Li / Schiemann, William P / Baskaran, Harihara / Lammerding, Jan / Egelhoff, Thomas T

    The Journal of cell biology

    2015  Volume 210, Issue 4, Page(s) 583–594

    Abstract: Non-muscle myosin II (NMII) is reported to play multiple roles during cell migration and invasion. However, the exact biophysical roles of different NMII isoforms during these processes remain poorly understood. We analyzed the contributions of NMIIA and ...

    Abstract Non-muscle myosin II (NMII) is reported to play multiple roles during cell migration and invasion. However, the exact biophysical roles of different NMII isoforms during these processes remain poorly understood. We analyzed the contributions of NMIIA and NMIIB in three-dimensional (3D) migration and in generating the forces required for efficient invasion by mammary gland carcinoma cells. Using traction force microscopy and microfluidic invasion devices, we demonstrated that NMIIA is critical for generating force during active protrusion, and NMIIB plays a major role in applying force on the nucleus to facilitate nuclear translocation through tight spaces. We further demonstrate that the nuclear membrane protein nesprin-2 is a possible linker coupling NMIIB-based force generation to nuclear translocation. Together, these data reveal a central biophysical role for NMIIB in nuclear translocation during 3D invasive migration, a result with relevance not only to cancer metastasis but for 3D migration in other settings such as embryonic cell migration and wound healing.
    MeSH term(s) Active Transport, Cell Nucleus ; Animals ; Biomechanical Phenomena ; Cell Line, Tumor ; Cell Movement ; Cell Nucleus/physiology ; Mice ; Nerve Tissue Proteins/metabolism ; Nonmuscle Myosin Type IIB/physiology ; Nuclear Proteins/metabolism
    Chemical Substances Nerve Tissue Proteins ; Nuclear Proteins ; Syne2 protein, mouse ; Nonmuscle Myosin Type IIB (EC 3.6.1.-)
    Language English
    Publishing date 2015-08-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.201502039
    Database MEDical Literature Analysis and Retrieval System OnLINE

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