Expression of p27Kip1, a cell cycle repressor protein, is inversely associated with potential carcinogenic risk in the genetic rodent models of obesity and long-lived Ames dwarf mice

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.

Magnolol Causes Alterations in the Cell Cycle in Androgen Insensitive Human Prostate Cancer CellsIn Vitroby Affecting Expression of Key Cell Cycle Regulatory Proteins

“…In their examination of the effects of honokiol on human prostate cancer cells in vitro, Hahm and Singh (24) found that expression of p21 increased in PC3 cells exposed to honokiol up to 8 h of exposure and subsequently decreased to basal levels thereafter, returning to levels comparable to the control by 24 h. As a result, protein expression of p21 and p27 was examined in DU145 and PC3 cells after 6 h exposure to magnolol, where both proteins trended toward increased expression with p27 showing a significant increase at 80 mM at the 6-h time point in both cell lines. Eto (29) found that p27 was inversely related to carcinogenic risk in vivo in mouse models, concluding that a loss of p27 increased the chance of these mice developing cancer. Similarly to the present study, Lee et al (11) observed an increase in p27 expression and no change in p21 expression in human urinary bladder cancer cells in vitro after exposure to magnolol.…”

Reduced growth hormone signaling and methionine restriction: interventions that improve metabolic health and extend life span

“…Plasma leptin levels are lower, likely due to the reduction in fat mass initiated by the restricted diets, while serum cholesterol and triglycerides are also decreased in rats on methionine‐restricted diets compared to animals fed normal chow . Similarly, Ames and Snell dwarf mice exhibit higher plasma adiponectin levels and low cholesterol, triglyceride, and free fatty acid levels , . Adiponectin levels remained higher in dwarf mice even following GH treatment .…”

“…30,55 Similarly, Ames and Snell dwarf mice exhibit higher plasma adiponectin levels and low cholesterol, triglyceride, and free fatty acid levels. 44,[56][57][58][59] Adiponectin levels remained higher in dwarf mice even following GH treatment. 44 The level of circulating leptin was not found to be different between genotypes in young females or adult males, but leptin was lower in adult and old female dwarfs compared to age-matched wild-type females.…”

“…78 Many components of the electron transport chain are upregulated (mRNA, protein, or activity) in Ames mice, while in mice fed methionine-restricted diets, many of these oxidative phosphorylation components are decreased or unchanged (Brown-Borg, unpublished observations). 58,[79][80][81] In methioninerestricted human fibroblasts, mild uncoupling of respiration (decreased RCR) is observed along with decreased ROS production and a decrease in complex IV activity because of a decrease in the mitochondrially encoded complex IV subunit COX1. 82 Dietary methionine restriction decreases mitochondrial ROS generation and oxidative damage to proteins and DNA.…”

Obesity and renal cancer

“…Thus, the progeny of LEP-signaling (ob/ob or db/db) mice crossed with MTTV-TGFα mice (the latter or which are prone to undergo spontaneous mammary carcinogenesis) do not develop mammary tumors 15 , 16 . Several carcinogenic actions have been attributed to LEP, including the modulation of cell cycle-regulatory proteins as cyclin D1 and G, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase inhibitor 1A (CDKN1A, best known as p21 CIP1 ), CDKN1B (best known as p27 KIP1 ), and CDKN2A (best known as p16 INK4A ) and transforming growth factor β1 (TGFβ1), resulting in the acceleration of cancer cell growth 17 , 18 . LEP also sustains angiogenesis.…”