Abstract
The loss of tuberin, the tuberous sclerosis-2 (Tsc-2) gene product, is associated with cytoplasmic mislocalization of p27 in uterine leiomyomas derived from Eker rats (Tsc-2 EK/+) and in human metastatic renal cell carcinoma tissue. Signaling associated with cytoplasmic mislocalization of p27 in renal cancer is relatively unknown. Renal tumors derived from 2,3,5-tris-(glutathion-Syl) hydroquinone (TGHQ)-treated Tsc-2 EK/+ rats, and null for tuberin, display elevated nuclear and cytosolic p27, with parallel increases in cytosolic cyclin D1 levels. Similar changes are observed in TGHQtransformed renal epithelial cells derived from Tsc-2 EK/+ rats (QTRRE cells), which, in addition to the cytoplasmic mislocalization of p27 and cyclin D1, exhibit high ERK, B-Raf, and Raf-1 kinase activity. Renal tumor xenografts, derived from subcutaneous injection of QTRRE cells into nude mice, also display increases in cytosolic mislocalization of p27 and cyclin D1. Dibutyryl cAMP and/or phosphodiesterase inhibitors (PIs; pentoxifylline or theophylline) increase Rap1B activation, B-Raf kinase activity, and cytosolic p27/ cyclinD1 protein levels inQTRREcells. Inhibition of Raf kinases with either sorafenib or B-Raf small interfering RNA (siRNA) caused a mitogen-activated protein kinase-mediated downregulation of p27. Moreover, decreases in cyclinD1 were also associated with p27 siRNA knockdown in QTRRE cells. Finally, theophylline-mediated increases in p27 and cyclin D1 were attenuated by sorafenib, which modulated Raf/MEK/ERK signaling. Collectively, these data suggest that the cAMP/Rap1B/B-Raf pathway modulates the expression of p27 and the cytoplasmic mislocalization of p27-cyclin D1 in tuberous sclerosis gene-regulated-renal cancer. Therefore, the loss of tuberin and engagement of the cAMP pathway may independently direct p27-cyclin D1 cytosolic stabilization during renal tumor formation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 361-371 |
| Number of pages | 11 |
| Journal | Toxicological Sciences |
| Volume | 122 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 2011 |
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Keywords
- B-raf
- cAMP
- Cyclin D1
- p27
- Quinol-thioether
- Renal cell carcinoma
ASJC Scopus subject areas
- Toxicology
Cite this
cAMP-dependent cytosolic mislocalization of p27 kip-Cyclin D1 during quinol-thioether-induced tuberous sclerosis renal cell carcinoma. / Cohen, Jennifer D.; Tham, Kimberly Y.; Mastrandrea, Nicholas J.; Gallegos, Alfred C.; Monks, Terrence; Lau, Serrine.
In: Toxicological Sciences, Vol. 122, No. 2, 08.2011, p. 361-371.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - cAMP-dependent cytosolic mislocalization of p27 kip-Cyclin D1 during quinol-thioether-induced tuberous sclerosis renal cell carcinoma
AU - Cohen, Jennifer D.
AU - Tham, Kimberly Y.
AU - Mastrandrea, Nicholas J.
AU - Gallegos, Alfred C.
AU - Monks, Terrence
AU - Lau, Serrine
PY - 2011/8
Y1 - 2011/8
N2 - The loss of tuberin, the tuberous sclerosis-2 (Tsc-2) gene product, is associated with cytoplasmic mislocalization of p27 in uterine leiomyomas derived from Eker rats (Tsc-2 EK/+) and in human metastatic renal cell carcinoma tissue. Signaling associated with cytoplasmic mislocalization of p27 in renal cancer is relatively unknown. Renal tumors derived from 2,3,5-tris-(glutathion-Syl) hydroquinone (TGHQ)-treated Tsc-2 EK/+ rats, and null for tuberin, display elevated nuclear and cytosolic p27, with parallel increases in cytosolic cyclin D1 levels. Similar changes are observed in TGHQtransformed renal epithelial cells derived from Tsc-2 EK/+ rats (QTRRE cells), which, in addition to the cytoplasmic mislocalization of p27 and cyclin D1, exhibit high ERK, B-Raf, and Raf-1 kinase activity. Renal tumor xenografts, derived from subcutaneous injection of QTRRE cells into nude mice, also display increases in cytosolic mislocalization of p27 and cyclin D1. Dibutyryl cAMP and/or phosphodiesterase inhibitors (PIs; pentoxifylline or theophylline) increase Rap1B activation, B-Raf kinase activity, and cytosolic p27/ cyclinD1 protein levels inQTRREcells. Inhibition of Raf kinases with either sorafenib or B-Raf small interfering RNA (siRNA) caused a mitogen-activated protein kinase-mediated downregulation of p27. Moreover, decreases in cyclinD1 were also associated with p27 siRNA knockdown in QTRRE cells. Finally, theophylline-mediated increases in p27 and cyclin D1 were attenuated by sorafenib, which modulated Raf/MEK/ERK signaling. Collectively, these data suggest that the cAMP/Rap1B/B-Raf pathway modulates the expression of p27 and the cytoplasmic mislocalization of p27-cyclin D1 in tuberous sclerosis gene-regulated-renal cancer. Therefore, the loss of tuberin and engagement of the cAMP pathway may independently direct p27-cyclin D1 cytosolic stabilization during renal tumor formation.
AB - The loss of tuberin, the tuberous sclerosis-2 (Tsc-2) gene product, is associated with cytoplasmic mislocalization of p27 in uterine leiomyomas derived from Eker rats (Tsc-2 EK/+) and in human metastatic renal cell carcinoma tissue. Signaling associated with cytoplasmic mislocalization of p27 in renal cancer is relatively unknown. Renal tumors derived from 2,3,5-tris-(glutathion-Syl) hydroquinone (TGHQ)-treated Tsc-2 EK/+ rats, and null for tuberin, display elevated nuclear and cytosolic p27, with parallel increases in cytosolic cyclin D1 levels. Similar changes are observed in TGHQtransformed renal epithelial cells derived from Tsc-2 EK/+ rats (QTRRE cells), which, in addition to the cytoplasmic mislocalization of p27 and cyclin D1, exhibit high ERK, B-Raf, and Raf-1 kinase activity. Renal tumor xenografts, derived from subcutaneous injection of QTRRE cells into nude mice, also display increases in cytosolic mislocalization of p27 and cyclin D1. Dibutyryl cAMP and/or phosphodiesterase inhibitors (PIs; pentoxifylline or theophylline) increase Rap1B activation, B-Raf kinase activity, and cytosolic p27/ cyclinD1 protein levels inQTRREcells. Inhibition of Raf kinases with either sorafenib or B-Raf small interfering RNA (siRNA) caused a mitogen-activated protein kinase-mediated downregulation of p27. Moreover, decreases in cyclinD1 were also associated with p27 siRNA knockdown in QTRRE cells. Finally, theophylline-mediated increases in p27 and cyclin D1 were attenuated by sorafenib, which modulated Raf/MEK/ERK signaling. Collectively, these data suggest that the cAMP/Rap1B/B-Raf pathway modulates the expression of p27 and the cytoplasmic mislocalization of p27-cyclin D1 in tuberous sclerosis gene-regulated-renal cancer. Therefore, the loss of tuberin and engagement of the cAMP pathway may independently direct p27-cyclin D1 cytosolic stabilization during renal tumor formation.
KW - B-raf
KW - cAMP
KW - Cyclin D1
KW - p27
KW - Quinol-thioether
KW - Renal cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=80051685832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80051685832&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfr118
DO - 10.1093/toxsci/kfr118
M3 - Article
C2 - 21693435
AN - SCOPUS:80051685832
VL - 122
SP - 361
EP - 371
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 2
ER -