Understanding p27<sup>kip1</sup>Deregulation in Cancer: Downregulation or Mislocalizaiton?

Viglietto, Giuseppe; Motti, Maria Letizia; Fusco, Alfredo

doi:10.4161/cc.1.6.263

Cited by 120 publications

(107 citation statements)

References 65 publications

(126 reference statements)

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“…In support of this possibility in KO mice, we have not observed the alterations in ectodermal organ development mediated by expression of active AKT kinase in transgenic mouse epidermis (59). However, we have observed a preferential increase in total versus nuclear p27 content in these mice, in agreement with the cytoplasmic localization of p27 mediated by AKT phosphorylation observed in cancer cells (60). It is clear that the study of the mechanisms by which TR or thyroid hormone depletion reduces cyclin D1 expression in keratinocytes in vivo warrants further investigation.…”

Section: Discussionsupporting

confidence: 76%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

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The actions of thyroid hormones are mediated by binding to nuclear receptors, TR␣ 4 and TR␤, that act as ligand-dependent transcription factors by association, generally as heterodimers with retinoid X receptors, with thyroid hormone response elements located in regulatory regions of target genes (1). TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3-7).Studies with knock-out (KO) mice for TRs obtained by homologous recombination have indicated that KO mice for ␣1 and ␤ TR isoforms have different phenotypes (8 -10) and that the double KO mice, surprisingly, survive (11), indicating that these receptors are not required for viability. Although these animals show extreme resistance to thyroid hormones, they exhibit a milder phenotype than hypothyroid mice, indicating divergent consequences for hormone versus receptor deficiency for some actions.Although the skin is a target tissue for thyroid hormone action, no studies on the skin phenotype in TR KO mice have been reported. TR␣ and TR␤ mRNAs are present in the skin (12-15), and these receptors can regulate either positively or negatively the expression of selected keratins in cultured cells (16 -19). Clinical evidence (19 -27) as well as studies in hypothyroid mice and rats (28 -30) also suggest that thyroid hormones could be involved in epidermal proliferation and differentiation, hair growth, and wound healing besides affecting the function of dermal fibroblasts. A question emerging from these studies is how to distinguish between effects due to altered thyroid hormone levels and effects due to expression of specific TR isoforms.The TR KO mice represent an excellent model for the analysis of the role of these receptors in the skin and its response to hyperproliferative stimuli. Topical application of 12-O-tetradecanolyphorbol-13-acetate (TPA) to mouse skin is a well known model for induction of skin hyperproliferation and also promotes a strong inflammatory reaction that activates multiple immunostimulatory pathways. The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to

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Section: Discussionsupporting

confidence: 76%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

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“…Low levels of the p27 kip1 protein have been frequently found in human carcinomas, and these low levels directly correlate with both a high histological tumor grade and a poor outcome (Lloyd et al 1999). In several cases, the impairment of the p27 function is due to its cytoplasmic mislocalization induced by AKT activation (Viglietto et al 2002, Motti et al 2005, Chu et al 2008. Also in thyroid malignant neoplasias, the impairment of the p27 function is very frequent: a reduction in p27 kip1 protein levels has been previously described in 10 out of 28 papillary carcinomas, 3 out of 9 follicular carcinomas, and 6 out of 8 anaplastic carcinomas.…”

Section: Introductionmentioning

confidence: 99%

Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

Fedele¹,

Palmieri²,

Chiappetta³

et al. 2009

Endocrine-Related Cancer

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Impairment of the p27 kip1 function, caused by a drastic reduction of its expression or cytoplasmic mislocalization, has been frequently observed in thyroid carcinomas. To understand the role of p27 kip1 impairment in thyroid carcinogenesis, we investigated the consequences of the loss of p27 kip1 expression in the context of a mouse modeling of papillary thyroid cancer, expressing the TRK-T1 oncogene under the transcriptional control of thyroglobulin promoter. We found that double mutant mice homozygous for a p27 kip1 null allele (TRK-T1/p27 K/K ) display a higher incidence of papillary thyroid carcinomas, with a shorter latency period and increased proliferation index, compared with p27 kip1 wild-type compounds (TRK-T1/p27 C/C ). Consistently, double mutant mice heterozygous for a p27 kip1 null allele (TRK-T1/p27 C/K ) show an incidence of thyroid carcinomas that is intermediate between TRK-T1/p27 K/K and TRK-T1/p27 C/C mice. Therefore, our findings suggest a dose-dependent role of p27 kip1 function in papillary thyroid cancer development.

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“…FASN activity interferes in cell cycle control and downregulates the cyclin-dependent kinase inhibitor p27 Kip1 . As a consequence, FASN has been proposed to promote adipocyte hyperplasia and obesity and cancer development (28,29).…”

Section: Articles Geneticsmentioning

confidence: 99%

Val1483Ile in FASN Gene Is Linked to Central Obesity and Insulin Sensitivity in Adult White Men

Moreno-Navarrete¹,

Botas²,

Valdés³

et al. 2009

Obesity

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The Val1483Ile polymorphism in the human fatty acid synthase (FASN) gene is located within the interdomain region of the FASN close to the two dynamic active centers of the FASN enzyme and putatively affects FASN action. We aimed to evaluate the association of this polymorphism with obesity phenotypes, insulin sensitivity, and adipose tissue FASN activity in adult white subjects. The polymorphism was evaluated in association with metabolic variables in two independent studies: in a case–control study of 457 men (229 with normal glucose tolerance (NGT) and 228 with altered glucose tolerance (AGT)); and in 600 population‐based NGT subjects (274 men and 326 women). Adipose tissue FASN activity was analyzed using the method of Nepokroeff. The Ile variant was associated with a lower waist‐to‐hip ratio (WHR) and a lower increase in weight over a 7‐year period in NGT men. In a subset of 147 men, carriers of the Ile variant showed significantly increased insulin sensitivity. BMI (P < 0.001), WHR (P = 0.03), and Val1483Ile (P = 0.03), contributed independently to 37% of insulin sensitivity variance. In men from the population‐based study, the Ile variant was associated with a lower BMI, WHR, fasting glucose, and systolic blood pressure compared with carriers of the Val variant. In agreement with these results, the adipose tissue FASN activity was significantly lower in subjects with the Ile variant (P = 0.01). In summary, adult white men with the Ile 1483 variant of the FASN gene seem protected from developing central obesity through decreased adipose tissue FASN activity.

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Understanding p27^kip1Deregulation in Cancer: Downregulation or Mislocalizaiton?

Cited by 120 publications

References 65 publications

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

Val1483Ile in FASN Gene Is Linked to Central Obesity and Insulin Sensitivity in Adult White Men

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Understanding p27kip1Deregulation in Cancer: Downregulation or Mislocalizaiton?

Cited by 120 publications

References 65 publications

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

Val1483Ile in FASN Gene Is Linked to Central Obesity and Insulin Sensitivity in Adult White Men

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Understanding p27^kip1Deregulation in Cancer: Downregulation or Mislocalizaiton?