29 research outputs found
Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity
It is widely accepted that reactive oxygen species (ROS) promote tumorigenesis. However, the exact mechanisms are still unclear. As mice lacking the peroxidase peroxiredoxin1 (Prdx1) produce more cellular ROS and die prematurely of cancer, they offer an ideal model system to study ROS-induced tumorigenesis. Prdx1 ablation increased the susceptibility to Ras-induced breast cancer. We, therefore, investigated the role of Prdx1 in regulating oncogenic Ras effector pathways. We found Akt hyperactive in fibroblasts and mammary epithelial cells lacking Prdx1. Investigating the nature of such elevated Akt activation established a novel role for Prdx1 as a safeguard for the lipid phosphatase activity of PTEN, which is essential for its tumour suppressive function. We found binding of the peroxidase Prdx1 to PTEN essential for protecting PTEN from oxidation-induced inactivation. Along those lines, Prdx1 tumour suppression of Ras- or ErbB-2-induced transformation was mediated mainly via PTEN
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Analysis of a Mouse Skin Model of Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis. They did develop a prominent skin phenotype with marked thickening of the dermis with accumulation of mast cells, that was minimally responsive to systemic rapamycin therapy, and was quite different from the pathology seen in human TSC skin lesions. Recombination and loss of Tsc1 was demonstrated in skin fibroblasts in vivo and in cultured skin fibroblasts. Loss of Tsc1 in fibroblasts in mice does not lead to a model of angiomyolipoma or lymphangioleiomyomatosis
Effect of chronic hypoxia on contents of urotensin II and its functional receptors in rat myocardium
Increased mast cells and fat necrosis are seen in the skin of <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice.
<p>A. High power images (400x magnification) of <i>Tsc1cc</i> and <i>Tsc1ccFsp-cre+</i> mouse skin at age 1 year is shown. Upper panel, chloroacetate esterase stain to highlight mast cells. Bottom panel, H&E stain showing fat necrosis, inset at 1000x. B. Quantification of mast cells per high-powered field (400x) as assessed by dermatopathologist (SG). Mast cells are significantly increased in both dorsal and ventral skin of Tsc1<sup>cc</sup>FspCre1+ mice compared to Tsc1cc mice. n = 3–9 for each measurement; mice had ages 8–13 months. C. Quantification of blood vessel density per high-powered field (400x) as assessed by dermatopathologist (SG). There is a possible trend toward more vessels in the mutant mouse skin. n = 2–4 for each measurement; mice had ages 8–13 months.</p
Response of the skin of <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice to one month treatment with rapamycin.
<p>A. Low and high power images of <i>Tsc1ccFsp-cre+</i> mouse skin at age 1 year is shown. Upper panel, H&E stain, with dermis indicated. Lower panel, chloroacetate esterase stain highlights mast cells. B-D. Quantification of epidermis and dermis thickness, and mast cell count per high-powered field (400x) as assessed by dermatopathologist (SG).</p
Skin histology in <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice.
<p>A. Representative skin H&E sections are shown for mice of each genotype at 1 year of age. All images shown are taken at 40x magnification. Top panel is dorsal and the bottom panel is ventral skin. Several layers are indicated in selected images, including dermis, hypodermis, and muscle layers. Note the increase in the dermal thickness and marked reduction in the hypodermis in <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice compared to <i>Tsc1</i><sup><i>cc</i></sup> mice. B, C. Quantitation of epidermis (B) and dermis (C) thickness is shown for control (solid circles) and Tsc1ccFsp-cre+ (solid squares) mice. Note the increase in both epidermal and dermal thickness, which is statistically significant in all cases except control vs. mutant dorsal epidermis. n = 10–14 for each measurement; mice had ages 8–13 months.</p
Identification of Cre expression and mTORC1 activation in the skin of <i>Tsc1ccFsp-cre+</i> mice.
<p>Confocal microscopy fused images (100x) are shown with nuclear (DAPI, blue), Cre (Anti-Cre antibody, green), and pS6(S235/236) (antibody, red) are shown. Multiple cells with appearance of fibroblasts are seen in the lower dermis of the mutant <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mouse skin, that stain with both red and green stains (yellow, indicated by arrow heads). Some of these cells are shown at higher magnification in the inset in the upper right corner (600x). A similar region of the control mouse skin shows no staining.</p
Survival and gross skin features of <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice.
<p>A. Survival curve of mice of various genotypes. Note reduced survival of <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice in comparison to other genotypes (p<0.0001). The median survival of <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice is 338 days. Right, there was no major difference between the survival of female and male <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice (p = 0.2660). The median survival of females and males is 349 days and 304 days respectively. B. Pictures of mice of various genotypes are shown. Note the loose, somewhat wrinkled skin seen in the <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice in comparison to other genotypes. All mice shown had age 8 months. C. Additional pictures of mice at age 1 year, with two <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice on left and two <i>Tsc1</i><sup><i>cc</i></sup> mice on right. Note wrinkled loose skin on abdomen, blunt nose, and larger paws of the <i>Tsc1</i><sup><i>cc</i></sup><i>Fsp-cre+</i> mice in comparison to the <i>Tsc1</i><sup><i>cc</i></sup> mice.</p