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Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer.

Yee NS, Zhou W, Liang IC - Dis Model Mech (2010)

Bottom Line: The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth.TRPM7 is generally overexpressed in human pancreatic adenocarcinoma.Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu

ABSTRACT
Genetic analysis of pancreatic development has provided new insights into the mechanisms underlying the formation of exocrine pancreatic neoplasia. Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth. Positional cloning and allelic complementation have revealed that the swd mutations affect the transient receptor potential melastatin-subfamily member 7 (trpm7) gene, which encodes a divalent cation-permeable channel with kinase activity. Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene. The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth. TRPM7 is generally overexpressed in human pancreatic adenocarcinoma. TRPM7-deficient cells are impaired in proliferation and arrested in the G0-G1 phases of the cell division cycle. Supplementary Mg(2+) rescued the proliferative defect of the TRPM7-deficient cells. Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

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Related in: MedlinePlus

The swdp75fm mutation impairs exocrine pancreatic epithelial cell division and cell growth. (A) Cell-cycle analysis of the exocrine pancreatic epithelia in swdp75fm mutants and WT siblings at 72 hpf. % BrdU+ nuclei represent the proportion of cells in the S phase of the cell cycle. (B) Morphometric analysis of cell growth (area, in μm2, per cell) in the exocrine pancreatic epithelia of swdp75fm mutants and WT siblings on 3 and 5 dpf. Each value represents the mean + s.e.m. Statistical analysis was performed using Student’s t-test, with *P<0.05 considered statistically significant.
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f2-0040240: The swdp75fm mutation impairs exocrine pancreatic epithelial cell division and cell growth. (A) Cell-cycle analysis of the exocrine pancreatic epithelia in swdp75fm mutants and WT siblings at 72 hpf. % BrdU+ nuclei represent the proportion of cells in the S phase of the cell cycle. (B) Morphometric analysis of cell growth (area, in μm2, per cell) in the exocrine pancreatic epithelia of swdp75fm mutants and WT siblings on 3 and 5 dpf. Each value represents the mean + s.e.m. Statistical analysis was performed using Student’s t-test, with *P<0.05 considered statistically significant.

Mentions: The proliferative ability of exocrine pancreatic epithelial cells in the swd mutants was then examined for cell-cycle progression and cell growth. The proportion of epithelial cells in the S phase of the cell cycle was determined using 5-bromo-2′-deoxyuridine (BrdU) as a marker (Fig. 2A). Cell size as an indicator of growth was analyzed by morphometric determination of the surface area per cell (Fig. 2B). In the exocrine pancreas of the swdp75fm mutants, the mean proportion of nuclei that was immunoreactive for BrdU was significantly reduced, as compared with WT (28% vs 40%, respectively). This indicates that the ability of exocrine pancreatic epithelial cells to enter into S phase is impaired in swdp75fm mutants. Similarly, in swdp75fm mutants, the mean exocrine pancreatic epithelial cell growth at 3 dpf and 5 dpf (119 and 180 μm2/cell, respectively) was significantly lower than that in WT (176 and 456 μm2/cell, respectively). This suggests that exocrine pancreatic epithelial cell growth in the swd mutants is reduced and retarded. There was no increased apoptotic cell death in exocrine pancreas of either swd mutants or WT larvae at 3–5 dpf using the Apoptag assay (N.S.Y., unpublished). Taken together, these results suggest that the swd-locus-encoded protein is required for cell-cycle progression and growth of the exocrine pancreatic epithelia during morphogenesis.


Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer.

Yee NS, Zhou W, Liang IC - Dis Model Mech (2010)

The swdp75fm mutation impairs exocrine pancreatic epithelial cell division and cell growth. (A) Cell-cycle analysis of the exocrine pancreatic epithelia in swdp75fm mutants and WT siblings at 72 hpf. % BrdU+ nuclei represent the proportion of cells in the S phase of the cell cycle. (B) Morphometric analysis of cell growth (area, in μm2, per cell) in the exocrine pancreatic epithelia of swdp75fm mutants and WT siblings on 3 and 5 dpf. Each value represents the mean + s.e.m. Statistical analysis was performed using Student’s t-test, with *P<0.05 considered statistically significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046099&req=5

f2-0040240: The swdp75fm mutation impairs exocrine pancreatic epithelial cell division and cell growth. (A) Cell-cycle analysis of the exocrine pancreatic epithelia in swdp75fm mutants and WT siblings at 72 hpf. % BrdU+ nuclei represent the proportion of cells in the S phase of the cell cycle. (B) Morphometric analysis of cell growth (area, in μm2, per cell) in the exocrine pancreatic epithelia of swdp75fm mutants and WT siblings on 3 and 5 dpf. Each value represents the mean + s.e.m. Statistical analysis was performed using Student’s t-test, with *P<0.05 considered statistically significant.
Mentions: The proliferative ability of exocrine pancreatic epithelial cells in the swd mutants was then examined for cell-cycle progression and cell growth. The proportion of epithelial cells in the S phase of the cell cycle was determined using 5-bromo-2′-deoxyuridine (BrdU) as a marker (Fig. 2A). Cell size as an indicator of growth was analyzed by morphometric determination of the surface area per cell (Fig. 2B). In the exocrine pancreas of the swdp75fm mutants, the mean proportion of nuclei that was immunoreactive for BrdU was significantly reduced, as compared with WT (28% vs 40%, respectively). This indicates that the ability of exocrine pancreatic epithelial cells to enter into S phase is impaired in swdp75fm mutants. Similarly, in swdp75fm mutants, the mean exocrine pancreatic epithelial cell growth at 3 dpf and 5 dpf (119 and 180 μm2/cell, respectively) was significantly lower than that in WT (176 and 456 μm2/cell, respectively). This suggests that exocrine pancreatic epithelial cell growth in the swd mutants is reduced and retarded. There was no increased apoptotic cell death in exocrine pancreas of either swd mutants or WT larvae at 3–5 dpf using the Apoptag assay (N.S.Y., unpublished). Taken together, these results suggest that the swd-locus-encoded protein is required for cell-cycle progression and growth of the exocrine pancreatic epithelia during morphogenesis.

Bottom Line: The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth.TRPM7 is generally overexpressed in human pancreatic adenocarcinoma.Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu

ABSTRACT
Genetic analysis of pancreatic development has provided new insights into the mechanisms underlying the formation of exocrine pancreatic neoplasia. Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth. Positional cloning and allelic complementation have revealed that the swd mutations affect the transient receptor potential melastatin-subfamily member 7 (trpm7) gene, which encodes a divalent cation-permeable channel with kinase activity. Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene. The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth. TRPM7 is generally overexpressed in human pancreatic adenocarcinoma. TRPM7-deficient cells are impaired in proliferation and arrested in the G0-G1 phases of the cell division cycle. Supplementary Mg(2+) rescued the proliferative defect of the TRPM7-deficient cells. Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

Show MeSH
Related in: MedlinePlus