Abstract
Introduction
The association of genetic rodent models of obesity and cancer still remains a controversial
issue. Although this controversy has largely been resolved in recent years for homozygous
leptin receptor-deficient obese Zucker rats and homozygous long-lived Ames dwarf mice,
it is still unresolved for homozygous leptin-deficient obese ob/ob mice.
Objective
The objective of the present study described below was to investigate whether the
expression of the cell cycle repressor protein p27(Kip1) is (a) down-regulated in
the tumor-free homozygous leptin receptor-deficient obese Zucker rats as well as tumor-free
homozygous leptin-deficient obese ob/ob mice and (b) up-regulated in the tumor-free
homozygous long-lived Ames dwarf mice.
Methods
To achieve this objective, we first performed western immunoblot analysis of the hepatic
expression of p27. We then performed western immunoblot analysis and proteomic analysis
of the hepatic expression of the proteins involved in the upstream molecular signaling
pathways for the expression of p27. Lastly, we analyzed the serum levels of glucose,
insulin, and branched-chain amino acids, all of which have been shown to regulate,
causally and inversely, the expression of p27.
Results/Conclusions
The results indicated that the hepatic expression of p27 was down-regulated in the
homozygous leptin receptor-deficient obese Zucker rats and up-regulated in the homozygous
long-lived Ames dwarf mice as expected. We also found that the hepatic expression
of p27 was down-regulated in the homozygous leptin-deficient obese ob/ob mice. This
last observation was not completely consistent with all of the results of the published
studies where homozygous leptin-deficient obese ob/ob mice were used.
Abbreviations:
4E-BP1 (eukaryotic translation initiation factor 4E binding protein 1), AICAR (5-amino-4-imidazolecarboxamide riboside), AMPK (5′-AMP-activated protein kinase), CDI (cyclin-dependent kinase inhibitor), CDK (cyclin-dependent kinase), ERK (ERK MAP kinase), GAPDH (glyceraldehydes phosphate dehydrogenase), H & E staining (hematoxylin and eosin staining), MALDI (matrix-assisted laser desorption/ionization), MAPK (mitogen-activated protein kinase), MEK (mitogen-activated protein (MAP) kinase kinase), MNK (MAP kinase interacting kinase), MNU (N-methyl-N-nitrosourea), MS (mass spectrometry), mTOR (mammalian target of rapamycin), nano LC-MS/MS (nano liquid chromatography–tandem mass spectrometry), p21 (p21Cip1/Waf1), p27 (p27Kip1), PI3K (phosphoinositide 3-kinase), PKB (protein kinase B), RTK (receptor tyrosine kinase), S6K (p70 S6 kinase), TOF (time-of-flight), TSC (tuberous sclerosis complex)Keywords
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References
- Effects of obesity on serum insulin growth factor 1 (IGF-1) levels in lean and obese female Zucker rats following DMBA treatment.FASEB J. 2005; 19: A993
- Effects of obesity on serum adiponectin levels and breast cancer development in lean and obese female Zucker rats following DMBA treatment.FASEB J. 2005; 19: A993
- Obesity promotes DMBAinduced mammary tumor development in female Zucker rats.FASEB J. 2005; 19: A774
- Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female Zucker rats.Breast Cancer Res. 2005; 7: R627-R633
- Effects of obesity on serum DHEA and DHEA sulfate levels using the obese Zucker rat as a model for breast cancer development.Obesity. 2006; 14: A134
- Obesity increases the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in ovariectomized Zucker rat.Int J Oncol. 2007; 30: 557-563
- Metabolic phenotype of the DMBA-induced mammary tumor in obese female Zucker rats.Am Assoc Cancer Res. 2005; 46: 6074
- Prostate cancer cell proliferation and angiogenesis in different obese mice models.Int J Exp Path. 2010; 91: 374-386
- Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival.Endocr Relat Cancer. 2011; 18: 491-503
- Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity.J Gerontol Ser A. 2003; 58: B291-B296
- Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice.J Gerontol Ser A. 2005; 60: 293-300
- Carcinogenesis in the pituitary of dwarf mouse. The response to dimethylbenzanthracene applied to the skin.Br J Cancer. 1961; 15: 257-262
- Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer.Breast Cancer Res. 2004; 6: 13-21
- Nutritional and chemopreventive anti-cancer agents up-regulate expression of p27Kip1, a cyclin-dependent kinase inhibitor, in mouse JB6 epidermal and human MCF7, MDA-MB-321 and AU565 breast cancer cells.Cancer Cell Int. 2006; 6: 1-19
- Upstream molecular signaling pathways of p27(Kip1) expression: effects of 4-hydroxytamoxifen, dexamethasone, and retinoic acids.Cancer Cell Int. 2010; 10: 1-19
- Upstream molecular signaling pathways of p27(Kip1) expression in human breast cancer cells in vitro: differential effects of 4-hydroxytamoxifen and deficiency of either D-(+)-glucose or L-leucine.Cancer Cell Int. 2011; 11: 1-17
- Cell cycle-dependent translation of p27 involves a responsive element in its 5′-UTR that overlaps with a uORF.Hum Mol Genet. 2003; 12: 1767-1779
- Repression of p27(kip1) synthesis by PDGF in balb/c 3 T3 cells.Mol Cell Biol. 1996; 16: 4327-4336
- Translational control of p27Kip1 accumulation during the cell cycle.Science. 1996; 71: 1861-1864
- Enhanced ribosomal association of p27(Kip1) mRNA is a mechanism contributing to accumulation during growth arrest.J Biol Chem. 1997; 272: 7093-7098
- A second RING to destroy p27Kip1.Nature Cell Biol. 2004; 6: 1153-1155
- Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27.Science. 1995; 269: 682-685
- Degradation of p27(Kip1) at the G(0)–G(1) transition mediated by a Skp2-independent ubiquitination pathway.J Biol Chem. 2001; 276: 48937-48943
- A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase.Nature. 2001; 413: 323-327
- Formation of p27-CDK complexes during the human mitotic cell cycle.Cell Growth Differ. 1996; 7: 135-146
- p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis.EMBO J. 2001; 20: 6672-6682
- Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.Nat Med. 2002; 8: 1136-1144
- PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest.Nat Med. 2002; 8: 1153-1160
- PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization.Nat Med. 2002; 8: 1145-1152
- CRM1/RAN-mediated nuclear export of p27Kip1 involves a nuclear export signal and links p27 export and proteolysis.Mol Biol Cell. 2003; 14: 201-213
- Altered p27Kip1 phosphorylation, localization, and function in human epithelial cells resistant to transforming growth factor β-mediated G1 arrest.Mol Cell Biol. 2002; 22: 2993-3002
- p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.Cell. 2007; 128: 281-294
- Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy.Mol Cell Biol. 2009; 29: 2254-2263
- Hepatocyte nuclear factor-4α involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase.Diabetes. 2001; 50: 1515-1521
- Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders.Diabetes Metab. 2007; 33: 395-402
- Insulin prevents leptin inhibition of RM1 prostate cancer cell growth.Path Oncol Res. 2012; 18: 499-507
- Obesity in db and ob animals leads to impaired hepatic very low density lipoprotein secretion and differential secretion of apolipoprotein B-48 and B-100.J Lipid Res. 1997; 38: 1277-1278
- Adipocytokines and lipid levels in Ames dwarf and calorie-restricted mice.J Gerontol A Biol Sci Med Sci. 2006; 61: 323-331
Article info
Publication history
Published online: January 28, 2013
Accepted:
January 2,
2013
Received:
October 23,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
