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result sql = Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition.
Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition.
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char = r;code = 114
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char = (;code = 40
char = 2;code = 50
char = );code = 41
char = D;code = 68
char = (;code = 40
char = 3;code = 51
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char = t;code = 116
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char = n;code = 110
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char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
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char = .;code = 46
char = ;code = 32
char = R;code = 82
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char = u;code = 117
char = c;code = 99
char = t;code = 116
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char = o;code = 111
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = C;code = 67
char = D;code = 68
char = K;code = 75
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char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
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char = b;code = 98
char = y;code = 121
char = ;code = 32
char = 1;code = 49
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char = 2;code = 50
char = 5;code = 53
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char = O;code = 79
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char = );code = 41
char = (;code = 40
char = 2;code = 50
char = );code = 41
char = D;code = 68
char = (;code = 40
char = 3;code = 51
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char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = s;code = 115
char = o;code = 111
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char = i;code = 105
char = a;code = 97
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char = e;code = 101
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char = w;code = 119
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char = t;code = 116
char = h;code = 104
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char = d;code = 100
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char = a;code = 97
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char = d;code = 100
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char = T;code = 84
char = 1;code = 49
char = 6;code = 54
char = 0;code = 48
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char = p;code = 112
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char = o;code = 111
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char = p;code = 112
char = h;code = 104
char = o;code = 111
char = r;code = 114
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char = l;code = 108
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char = ;code = 32
char = a;code = 97
char = ;code = 32
char = r;code = 114
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char = s;code = 115
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = e;code = 101
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char = w;code = 119
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = e;code = 101
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char = p;code = 112
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char = o;code = 111
char = s;code = 115
char = p;code = 112
char = h;code = 104
char = o;code = 111
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char = y;code = 121
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
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char = e;code = 101
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char = n;code = 110
char = u;code = 117
char = c;code = 99
char = l;code = 108
char = e;code = 101
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char = s;code = 115
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char = i;code = 105
char = s;code = 115
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = C;code = 67
char = D;code = 68
char = K;code = 75
char = 2;code = 50
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char = a;code = 97
char = c;code = 99
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char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = E;code = 69
char = c;code = 99
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char = o;code = 111
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char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = x;code = 120
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char = r;code = 114
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char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = y;code = 121
char = c;code = 99
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = E;code = 69
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = t;code = 116
char = o;code = 111
char = ;code = 32
char = o;code = 111
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char = e;code = 101
char = r;code = 114
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = 1;code = 49
char = ,;code = 44
char = 2;code = 50
char = 5;code = 53
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char = (;code = 40
char = O;code = 79
char = H;code = 72
char = );code = 41
char = (;code = 40
char = 2;code = 50
char = );code = 41
char = D;code = 68
char = (;code = 40
char = 3;code = 51
char = );code = 41
char = -;code = 45
char = m;code = 109
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char = d;code = 100
char = i;code = 105
char = a;code = 97
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char = e;code = 101
char = d;code = 100
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char = o;code = 111
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = m;code = 109
char = i;code = 105
char = c;code = 99
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char = m;code = 109
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char = s;code = 115
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char = o;code = 111
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char = a;code = 97
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char = a;code = 97
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char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = C;code = 67
char = D;code = 68
char = K;code = 75
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char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = a;code = 97
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char = l;code = 108
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = f;code = 102
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 1;code = 49
char = ,;code = 44
char = 2;code = 50
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char = O;code = 79
char = H;code = 72
char = );code = 41
char = (;code = 40
char = 2;code = 50
char = );code = 41
char = D;code = 68
char = (;code = 40
char = 3;code = 51
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char = ,;code = 44
char = ;code = 32
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char = t;code = 116
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char = e;code = 101
char = l;code = 108
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char = c;code = 99
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char = E;code = 69
char = ;code = 32
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char = b;code = 98
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char = i;code = 105
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char = C;code = 67
char = D;code = 68
char = K;code = 75
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char = w;code = 119
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char = e;code = 101
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char = f;code = 102
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char = );code = 41
char = (;code = 40
char = 2;code = 50
char = );code = 41
char = D;code = 68
char = (;code = 40
char = 3;code = 51
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char = .;code = 46
char = ;code = 32
char = S;code = 83
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char = m;code = 109
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char = l;code = 108
char = a;code = 97
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char = ;code = 32
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char = e;code = 101
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char = C;code = 67
char = D;code = 68
char = K;code = 75
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char = u;code = 117
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char = s;code = 115
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char = a;code = 97
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char = i;code = 105
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char = c;code = 99
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char = s;code = 115
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char = s;code = 115
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char = c;code = 99
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char = i;code = 105
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char = E;code = 69
char = ;code = 32
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char = p;code = 112
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char = r;code = 114
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char = i;code = 105
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char = l;code = 108
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char = e;code = 101
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char = s;code = 115
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char = a;code = 97
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char = c;code = 99
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char = o;code = 111
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char = 1;code = 49
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char = O;code = 79
char = H;code = 72
char = );code = 41
char = (;code = 40
char = 2;code = 50
char = );code = 41
char = D;code = 68
char = (;code = 40
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char = p;code = 112
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char = .;code = 46
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char = h;code = 104
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char = e;code = 101
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char = O;code = 79
char = H;code = 72
char = );code = 41
char = (;code = 40
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char = ;code = 32
char = C;code = 67
char = D;code = 68
char = K;code = 75
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char = T;code = 84
char = a;code = 97
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char = e;code = 101
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char = C;code = 67
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char = K;code = 75
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char = s;code = 115
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result sql = 1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), inhibits proliferation of a variety of cell types including adenocarcinoma of the prostate. We have previously shown that 1,25-(OH)(2)D(3) increases the stability of the cyclin-dependent kinase inhibitor p27(KIP1), decreases cyclin-dependent kinase 2 (CDK2) activity, and promotes G(1) phase accumulation in human prostate cancer cells. These effects correlate with cytoplasmic relocalization of CDK2. In this study, we investigated the role of CDK2 cytoplasmic relocalization in the antiproliferative effects of 1,25-(OH)(2)D(3). CDK2 was found to be necessary for prostate cancer cell proliferation. Although induced by 1,25-(OH)(2)D(3), the cyclin-dependent kinase inhibitor p27(KIP1) was dispensable for 1,25-(OH)(2)D(3)-mediated growth inhibition. Reduction in CDK2 activity by 1,25-(OH)(2)D(3) was associated with decreased T160 phosphorylation, a residue whose phosphorylation in the nucleus is essential for CDK2 activity. Ectopic expression of cyclin E was sufficient to overcome 1,25-(OH)(2)D(3)-mediated cytoplasmic mislocalization of CDK2 and all antiproliferative effects of 1,25-(OH)(2)D(3), yet endogenous levels of cyclin E or binding to CDK2 were not affected by 1,25-(OH)(2)D(3). Similarly, knockdown of the CDK2 substrate retinoblastoma, which causes cyclin E up-regulation, resulted in resistance to 1,25-(OH)(2)D(3)-mediated growth inhibition. Human prostate cancer cells resistant to growth inhibition by 1,25-(OH)(2)D(3) but retaining fully functional vitamin D receptors were developed. These cells did not exhibit 1,25-(OH)(2)D(3)-mediated cytoplasmic relocalization of CDK2. Targeting CDK2 to the nucleus of 1,25-(OH)(2)D(3)-sensitive cancer cells blocked G(1) accumulation and growth inhibition by 1,25-(OH)(2)D(3). These data establish central roles for CDK2 nuclear-cytoplasmic trafficking and cyclin E in the mechanism of 1,25-(OH)(2)D(3)-mediated growth inhibition in prostate cancer cells.

Publication: Endocrinology 2010 Mar ;151(3)::896-908. :doi: 10.1210/en.2009-1116.
Publication Date: 2010 Mar
Study Author(s): Flores, Omar;Wang, Zhengying;Knudsen, Karen E;Burnstein, Kerry L;
Institution: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, Miami, Florida 33136, USA.
Shortcut link to this study:
1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), inhibits proliferation of a variety of cell types including adenocarcinoma of the prostate. We have previously shown that 1,25-(OH)(2)D(3) increases the stability of the cyclin-dependent kinase inhibitor p27(KIP1), decreases cyclin-dependent kinase 2 (CDK2) activity, and promotes G(1) phase accumulation in human prostate cancer cells. These effects correlate with cytoplasmic relocalization of CDK2. In this study, we investigated the role of CDK2 cytoplasmic relocalization in the antiproliferative effects of 1,25-(OH)(2)D(3). CDK2 was found to be necessary for prostate cancer cell proliferation. Although induced by 1,25-(OH)(2)D(3), the cyclin-dependent kinase inhibitor p27(KIP1) was dispensable for 1,25-(OH)(2)D(3)-mediated growth inhibition. Reduction in CDK2 activity by 1,25-(OH)(2)D(3) was associated with decreased T160 phosphorylation, a residue whose phosphorylation in the nucleus is essential for CDK2 activity. Ectopic expression of cyclin E was sufficient to overcome 1,25-(OH)(2)D(3)-mediated cytoplasmic mislocalization of CDK2 and all antiproliferative effects of 1,25-(OH)(2)D(3), yet endogenous levels of cyclin E or binding to CDK2 were not affected by 1,25-(OH)(2)D(3). Similarly, knockdown of the CDK2 substrate retinoblastoma, which causes cyclin E up-regulation, resulted in resistance to 1,25-(OH)(2)D(3)-mediated growth inhibition. Human prostate cancer cells resistant to growth inhibition by 1,25-(OH)(2)D(3) but retaining fully functional vitamin D receptors were developed. These cells did not exhibit 1,25-(OH)(2)D(3)-mediated cytoplasmic relocalization of CDK2. Targeting CDK2 to the nucleus of 1,25-(OH)(2)D(3)-sensitive cancer cells blocked G(1) accumulation and growth inhibition by 1,25-(OH)(2)D(3). These data establish central roles for CDK2 nuclear-cytoplasmic trafficking and cyclin E in the mechanism of 1,25-(OH)(2)D(3)-mediated growth inhibition in prostate cancer cells.
PMID: 20147522

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