Analysis Of Candidate Genes Expected To Be Essential For Melanoma Surviving

Krivosheeva, Irina; Filatova, Alexandra; Moshkovskii, Sergei A.; Baranova, Ancha; Skoblov, Mikhail

doi:10.21203/rs.3.rs-43507/v2

Cited by 4 publications

(5 citation statements)

References 35 publications

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“…Depletion of this chaperone was shown to inhibit motility of breast and ovarian cancer cells, 27,29 but promoted migration of osteosarcoma and melanoma cells. 30,62 This resembles the reported opposite effects of NM-II inhibition on cell migration under different experimental conditions 50,63 and may reflect complex regulatory effects of UNC-45A-driven myofilament assembly in motile cells. We observed that loss of UNC-45A inhibited both collective migration of IEC sheets and individual cell passage through membrane pores (Figure 5A-H).…”

Section: Discussionsupporting

confidence: 71%

“…Generally, the roles of UNC‐45A in mammalian cell migration remain controversial. Depletion of this chaperone was shown to inhibit motility of breast and ovarian cancer cells, 27,29 but promoted migration of osteosarcoma and melanoma cells 30,62 50,63 and may reflect complex regulatory effects of UNC‐45A‐driven myofilament assembly in motile cells.…”

Section: Discussionmentioning

confidence: 98%

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A myosin chaperone, UNC‐45A, is a novel regulator of intestinal epithelial barrier integrity and repair

et al. 2022

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The actomyosin cytoskeleton serves as a key regulator of the integrity and remodeling of epithelial barriers by controlling assembly and functions of intercellular junctions and cell‐matrix adhesions. Although biochemical mechanisms that regulate the activity of non‐muscle myosin II (NM‐II) in epithelial cells have been extensively investigated, little is known about assembly of the contractile myosin structures at the epithelial adhesion sites. UNC‐45A is a cytoskeletal chaperone that is essential for proper folding of NM‐II heavy chains and myofilament assembly. We found abundant expression of UNC‐45A in human intestinal epithelial cell (IEC) lines and in the epithelial layer of the normal human colon. Interestingly, protein level of UNC‐45A was decreased in colonic epithelium of patients with ulcerative colitis. CRISPR/Cas9‐mediated knock‐out of UNC‐45A in HT‐29cf8 and SK‐CO15 IEC disrupted epithelial barrier integrity, impaired assembly of epithelial adherence and tight junctions and attenuated cell migration. Consistently, decreased UNC‐45 expression increased permeability of the Drosophila gut in vivo. The mechanisms underlying barrier disruptive and anti‐migratory effects of UNC‐45A depletion involved disorganization of the actomyosin bundles at epithelial junctions and the migrating cell edge. Loss of UNC‐45A also decreased contractile forces at apical junctions and matrix adhesions. Expression of deletion mutants revealed roles for the myosin binding domain of UNC‐45A in controlling IEC junctions and motility. Our findings uncover a novel mechanism that regulates integrity and restitution of the intestinal epithelial barrier, which may be impaired during mucosal inflammation.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 98%

A myosin chaperone, UNC‐45A, is a novel regulator of intestinal epithelial barrier integrity and repair

et al. 2022

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show abstract

Section: Discussionsupporting

confidence: 71%

Myosin chaperone, UNC‐45A, is a novel regulator of intestinal epithelial barrier integrity and repair

et al. 2022

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The intestinal epithelium creates a protective barrier separating the luminal content and the immune system in the gut. Leakiness of the intestinal epithelial barrier and inefficient healing of mucosal wounds represent common manifestations of inflammatory bowel diseases (IBD). Integrity of the gut barrier is mediated by different adhesive structures, including adherens junctions (AJ), tight junctions (TJ) and focal adhesion (FA). Functions of these adhesive structures depend on their association with the cortical actin cytoskeleton and particularly, to a major actin motor protein, non‐muscle myosin II (NM‐II). While biochemical mechanisms that regulate activity of NM‐II in epithelial cells have been extensively investigated, little is known about assembly of the contractile myosin structures at the epithelial adhesion sites. In this study, we focused on UNC‐45A, a cytoskeletal chaperone that is essential for proper folding of NM‐II heavy chains and myofilament assembly. We found abundant expression of UNC‐45A in human intestinal epithelial cell (IEC) lines and in the epithelial layer of the normal human colon. Interestingly, protein levels of UNC‐45A were decreased in colonic epithelium of patients with ulcerative colitis in parallel to diminished expression of NM‐IIA and NM‐IIC isoforms. CRISPR/Cas9‐mediated knock‐out of UNC‐45A in HT‐29 and SK‐CO15 IEC disrupted epithelial barrier integrity, impaired AJ and TJ assembly, and cell migration. Consistently, decreased UNC‐45 expression increased permeability of the Drosophila gut in vivo. The mechanisms underlying barrier disruptive and anti‐migratory effects of UNC‐45A depletion involved disorganization of the actomyosin bundles at epithelial junctions and the migrating cell edge. Loss of UNC‐45A also decreased contractile forces at epithelial junctions and matrix adhesions. Expression of deletion mutants revealed roles for the myosin binding domain of UNC‐45A in controlling IEC barrier function, junctional assembly and migration. Our findings uncover a novel mechanism that regulates integrity and restitution of the intestinal epithelial barrier, which may be impaired during mucosal inflammation.

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“…Generally, the roles of UNC-45A in mammalian cell migration remain controversial. Depletion of this chaperone was shown to inhibit motility of breast and ovarian cancer cells 27,29 , but promoted migration of osteosarcoma and melanoma cells 30,67 . This resembles the reported opposite effects of NM-II inhibition on cell migration under different experimental conditions 52,68 and may reflect complex regulatory effects of UNC-45A-driven myofilament assembly in motile cells.…”

Section: Discussionmentioning

confidence: 98%

A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair

Lechuga

Cartagena‐Rivera

Khan

et al. 2021

Preprint

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The actomyosin cytoskeleton serves as a key regulator of the integrity and remodeling of epithelial barriers by controlling assembly and functions of intercellular junctions and cell-matrix adhesions. While biochemical mechanisms that regulate activity of non-muscle myosin II (NM-II) in epithelial cells have been extensively investigated, little is known about assembly of the contractile myosin structures at the epithelial adhesion sites. UNC-45A is a cytoskeletal chaperone that is essential for proper folding of NM II heavy chains and myofilament assembly. We found abundant expression of UNC-45A in human intestinal epithelial cell (IEC) lines and in the epithelial layer of the normal human colon. Interestingly, protein levels of UNC-45A were decreased in colonic epithelium of patients with ulcerative colitis. CRISPR/Cas9-mediated knock-out of UNC-45A in HT-29 and SK-CO15 IEC disrupted epithelial barrier integrity, impaired assembly of epithelial adherence and tight junctions and attenuated cell migration. Consistently, decreased UNC-45 expression increased permeability of the Drosophila gut in vivo. The mechanisms underlying barrier disruptive and anti-migratory effects of UNC-45A depletion involved disorganization of the actomyosin bundles at epithelial junctions and the migrating cell edge. Loss of UNC-45A also decreased contractile forces at epithelial junctions and matrix adhesions. Expression of deletion mutants revealed roles for the myosin binding domain of UNC-45A in controlling IEC junctions and motility. Our findings uncover a novel mechanism that regulates integrity and restitution of the intestinal epithelial barrier, which may be impaired during mucosal inflammation.

show abstract

Analysis Of Candidate Genes Expected To Be Essential For Melanoma Surviving

Cited by 4 publications

References 35 publications

A myosin chaperone, UNC‐45A, is a novel regulator of intestinal epithelial barrier integrity and repair

A myosin chaperone, UNC‐45A, is a novel regulator of intestinal epithelial barrier integrity and repair

Myosin chaperone, UNC‐45A, is a novel regulator of intestinal epithelial barrier integrity and repair

A myosin chaperone, UNC-45A, is a novel regulator of intestinal epithelial barrier integrity and repair

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