Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland

Motti, Maria Letizia; Boccia, Angelo; Belletti, Barbara; Bruni, Paola; Troncone, Giancarlo; Cito, Letizia; Monaco, Mario; Chiappetta, Gennaro; Baldassarre, Gustavo; Palombini, Lucio; Viglietto, Giuseppe

doi:10.1038/sj.onc.1207055

Cited by 23 publications

(20 citation statements)

References 37 publications

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“…Indeed, Pten L/L ;TPO-Cre thyroids were characterized by highly phosphorylated p70S6K1 and S6 proteins, suggesting that PI3K activation is sufficient to stimulate this pathway. We also found that PI3K/Akt activation was associated with increased levels of both cyclin D1 and cyclin D3, consistent with previous data supporting their role in thyrocyte proliferation and human thyroid proliferative disorders (35,36).…”

Section: Discussionsupporting

confidence: 79%

Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis

Yeager¹,

et al. 2007

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Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, including multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain, in which Cre-mediated recombination is used to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by extremely enlarged follicles, in the presence of normal thyroid-stimulating hormone and T4 hormone levels. Loss of Pten resulted in a significant increase in the thyrocyte proliferative index, which was more prominent in the female mice, and in increased cell density in the female thyroid glands. Surprisingly, goitrogen treatment did not cause a substantial increase of the mutant thyroid size and increased only to some extent the proliferation index of the female thyrocytes, suggesting that a relevant part of the thyroidstimulating hormone-induced proliferation signals are funneled through the phosphatidylinositol-3-kinase (PI3K)/ Akt cascade. Although complete loss of Pten was not sufficient to cause invasive tumors, over two thirds of the mutant females developed follicular adenomas by 10 months of age, showing that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/Akt cascade is sufficient to stimulate continuous autonomous growth and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter. [Cancer Res 2007;67(3):959-66]

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Section: Discussionsupporting

confidence: 79%

Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis

Yeager¹,

et al. 2007

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“…Moreover, in both opposite situations, cAMP differentially regulates the activity and phosphorylation of CDK4 bound to cyclin D1 or to cyclin D3. Cyclin D3 is the predominant D-type cyclin in normal thyrocytes (Depoortere et al, 1998;Van Keymeulen et al, 1999;Motti et al, 2003;Paternot et al, 2006b). Although growth factors mostly activate cyclin D1-CDK4-p21 complexes, cyclin D3-CDK4 is specifically required and activated in the mitogenic stimulation by TSH and cAMP (Depoortere et al, 1998;Motti et al, 2003;Paternot et al, 2006a,b).…”

Section: Discussionmentioning

confidence: 99%

“…Cyclin D3 is the predominant D-type cyclin in normal thyrocytes (Depoortere et al, 1998;Van Keymeulen et al, 1999;Motti et al, 2003;Paternot et al, 2006b). Although growth factors mostly activate cyclin D1-CDK4-p21 complexes, cyclin D3-CDK4 is specifically required and activated in the mitogenic stimulation by TSH and cAMP (Depoortere et al, 1998;Motti et al, 2003;Paternot et al, 2006a,b). This crucially involves the cAMP-dependent phosphorylation of cyclin D3-bound CDK4 (Paternot et al, 2003Bockstaele et al, 2006b).…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP Inhibits the Proliferation of Thyroid Carcinoma Cell Lines through Regulation of CDK4 Phosphorylation

Rocha

Paternot

Coulonval

et al. 2008

MBoC

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How cyclic AMP (cAMP) could positively or negatively regulate G1 phase progression in different cell types or in cancer cells versus normal differentiated counterparts has remained an intriguing question for decades. At variance with the cAMP-dependent mitogenesis of normal thyroid epithelial cells, we show here that cAMP and cAMP-dependent protein kinase activation inhibit S-phase entry in four thyroid carcinoma cell lines that harbor a permanent activation of the Raf/ERK pathway by different oncogenes. Only in Ret/PTC1-positive TPC-1 cells did cAMP markedly inhibit the Raf/ERK cascade, leading to mTOR pathway inhibition, repression of cyclin D1 and p21 and p27 accumulation. p27 knockdown did not prevent the DNA synthesis inhibition. In the other cells, cAMP little affected these signaling cascades and levels of cyclins D or CDK inhibitors. However, cAMP differentially inhibited the pRb-kinase activity and T172-phosphorylation of CDK4 complexed to cyclin D1 or cyclin D3, whereas CDK-activating kinase activity remained unaffected. At variance with current conceptions, our studies in thyroid carcinoma cell lines and previously in normal thyrocytes identify the activating phosphorylation of CDK4 as a common target of opposite cell cycle regulations by cAMP, irrespective of its impact on classical mitogenic signaling cascades and expression of CDK4 regulatory partners. INTRODUCTIONCyclic AMP (cAMP) is the first identified intracellular mediator (second messenger) of hormone action. In the seventies and early eighties, the observation that cAMP elevations may inhibit cell proliferation in various established cell lines, mostly of tumoral origin, has prompted an intense scientific activity, even becoming the main paradigm of cell cycle regulation (Pastan and Johnson, 1974;Pastan et al., 1975;Friedman, 1976;Rebhun, 1977). More recent studies have ascribed the cell cycle inhibition by cAMP to the inhibition of several steps of the mitogenic cascades elicited by growth factors or oncogenic mutations (Roger et al., 1995;Stork and Schmitt, 2002;Dumaz and Marais, 2005). Most generally considered mechanisms include inhibition of ERK1/2 pathway by inhibitory phosphorylations of c-Raf by cAMP-dependent protein kinases (PKA; Cook and McCormick, 1993;Graves et al., 1993;Dumaz and Marais, 2003), leading to transcriptional repression of protooncogenic transcription factors (c-jun, c-myc, egr-1, . . .;Heldin et al., 1989;Mechta et al., 1989;Cowlen and Eling, 1992), repression of D-type cyclins (cyclin D1, cyclin D3; Cocks et al., 1992;Sewing et al., 1993;Ward et al., 1996;L'Allemain et al., 1997), and accumulation of the p27 kip1 CDK inhibitor Ward et al., 1996;van Oirschot et al., 2001;Kuiperij et al., 2005), which inhibits both CDK4 and CDK2 Kuiperij et al., 2005) and thus inactivating phosphorylations of pRb. Inhibition of cyclin D1-CDK4 activity by cAMP-dependent accumulation of p27 has been ascribed to p27 impairing the activating T172-phosphorylation of CDK4 by the constitutively active CDK-activating kinase (CAK, cyclin H-C...

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“…19 We previously demonstrated that cyclin D3 expression is rate-limiting for G 1 progression in thyroid follicular cells. 20 Subsequently, we validated cyclin D3 immunostaining in a large series of paraffin-embedded thyroid cancer tissues. 13 Cyclin D3 expression was associated specifically with Hurthle cell carcinoma and had a diffuse and intense nuclear staining pattern.…”

Section: -5mentioning

confidence: 99%

Cyclin D1 and D3 overexpression predicts malignant behavior in thyroid fine‐needle aspirates suspicious for Hurthle cell neoplasms

Troncone

Volante

Iaccarino

et al. 2009

Cancer Cytopathology

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BACKGROUND:Thyroid fine‐needle aspiration (FNA) samples that feature a follicular‐patterned, monotonous Hurthle (oncocytic) cell population cannot be diagnosed reliably. The authors of this report recently identified cyclin D3 overexpression on histologic sections of Hurthle cell carcinoma. In this study, they assessed the diagnostic value of cyclin D3 immunohistochemistry added to routine cytology.METHODS:Fifty‐one FNA samples that were suspicious for Hurtle cell neoplasia and that had histologic follow‐up (19 malignant cases) were examined. Cyclin D3 expression levels were evaluated in cell block preparations and were compared with levels of the closely related cyclin D1 protein.RESULTS:Greater than 25% positive cells were used as the cutoff point, as suggested by previous studies. Cyclin D1 and cyclin D3 were highly specific (100% for both) and fairly accurate (75% and 92%, respectively) in distinguishing between benign and malignant oncocytic lesions; the positive predictive value (PPV) for each was 100%. However, both cyclins D1 and D3 had low sensitivity (32% and 79%, respectively) and low negative predictive value (NPV) (71% and 89%, respectively). In contrast, by adopting balanced receiver operating characteristic‐derived positive cutoff values, cyclin D1 (≥6.5%) and cyclin D3 (≥7.5%) were found to be highly sensitive (100% for both) and accurate (90% and 94%, respectively); and the NPV was 100% for both. In contrast, cyclins D1 and D3 had low specificity (84% and 91%, respectively) and a low PPV (79% and 86%, respectively); however, these values improved in samples that were positive for both cyclins (sensitivity, 100%; specificity, 94%; PPV, 90%; NPV, 100%; and accuracy, 96%).CONCLUSIONS:Cyclin D3 increased the suspicion of malignancy in indeterminate oncocytic lesions; its diagnostic performance depended on the cutoff point used and was enhanced further when combined with cyclin D1. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.

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Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland

Cited by 23 publications

References 37 publications

Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis

Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis

Cyclic AMP Inhibits the Proliferation of Thyroid Carcinoma Cell Lines through Regulation of CDK4 Phosphorylation

Cyclin D1 and D3 overexpression predicts malignant behavior in thyroid fine‐needle aspirates suspicious for Hurthle cell neoplasms

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