Retinoid Targeting of Different D-Type Cyclins through Distinct Chemopreventive Mechanisms

Ma, Yan; Feng, Qing; Sekula, David; Diehl, J. Alan; Freemantle, Sarah J.; Dmitrovsky, Ethan

doi:10.1158/0008-5472.can-05-0370

Cited by 32 publications

(32 citation statements)

References 31 publications

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“…This indicates that ubiquitin-targeted proteasomal degradation of cyclin D1, Id2 or any other proliferation-promoting factor is unlikely to play a major role in mechanisms of the antiproliferative action of retinoids in human keratinocytes. It should be noted, however, that besides the use of different cell lines, retinoic acid concentrations used in experiments reported by Ma et al (2005) were about two orders of magnitude higher than those used in our study. It is conceivable that higher doses are required to activate the proteasomal regulatory pathway.…”

Section: Resultscontrasting

confidence: 63%

“…It has been reported that retinoic acid does not affect levels of cyclin D1 mRNA, but promotes the ubiquitination and consequent degradation of cyclin D1 protein, and that proteasomal inhibitors block retinoid-induced decline in cyclin D1 (Ma et al, 2005). In a different experimental system, glucocorticoid-induced decline in proliferation of neural stem cells was abrogated in the presence of 0.5 mM of a potent proteasomal inhibitor MG132, reflecting an involvement of the ubiquitin proteasomal pathway (Sundberg et al, 2006).…”

Section: Resultsmentioning

confidence: 97%

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Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

et al. 2007

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We investigated the effect of all-trans-retinoic acid (atRA) on proliferation in several human skin cell lines and found that antiproliferative potency of atRA correlated with the endogenous activity of canonical Wnt signaling. In HaCaT keratinocytes, we found that atRA significantly suppressed the expression of Id2, a member of the inhibitor of differentiation family of transcription factors that regulate cell growth and differentiation. However, no apparent change in the expression of other Wnt targets, like c-Myc or cyclin D1, was observed. Retinoid-induced Id2 gene suppression was associated with decreased levels of histone H3 and H4 acetylation and histone H3 Lys-4 methylation, and with recruitment of the LSD1 demethylase at the Wnt-response element (WRE) (TCF/LEF-binding site), in the Id2 gene promoter. None of such changes was detected at the WRE of c-Myc and cyclin D1 gene promoters. Inhibition of Id2 by short interfering RNA (siRNA) had a similar effect on the proliferation of HaCaT cells as exposure to atRA, whereas anti-b-catenin siRNA significantly inhibited its antiproliferative effect. These data suggest that downregulation of Id2 gene expression through transcriptional convergence between Wnt and retinoid signaling pathways underlies the antiproliferative effect of retinoids in keratinocytes, and provide evidence of gene-targeted crosstalk between signaling pathways.

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Section: Resultscontrasting

confidence: 63%

Section: Resultsmentioning

confidence: 97%

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

et al. 2007

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“…BEAS-2B immortalized HBE cells were cultured in serum-free LHC-9 medium (Biofluids, Rockville, MD) as described (32). Nontumorigenic murine C10 alveolar type II epithelial cells (33) were cultured in CMRL 1066 medium (Life Technologies, Grand Island, NY) supplemented with 10% FBS, 2 mM L-glutamine, 100 units/ml penicillin, and 100 g/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…The GL2 siRNA (Dharmacon, Lafayette, CO) served as a control. Transfection was performed as described (32). Viable BEAS-2B cells were measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (34).…”

Section: Methodsmentioning

confidence: 99%

Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas

Ma¹,

Fiering

Black

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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121

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Cyclin E is a critical G1-S cell cycle regulator aberrantly expressed in bronchial premalignancy and lung cancer. Cyclin E expression negatively affects lung cancer prognosis. Its role in lung carcinogenesis was explored. Retroviral cyclin E transduction promoted pulmonary epithelial cell growth, and small interfering RNA targeting of cyclin E repressed this growth. Murine transgenic lines were engineered to mimic aberrant cyclin E expression in the lung. Wild-type and proteasome degradation-resistant human cyclin E transgenic lines were independently driven by the human surfactant C (SP-C) promoter. Chromosome instability (CIN), pulmonary dysplasia, sonic hedgehog (Shh) pathway activation, adenocarcinomas, and metastases occurred. Notably, high expression of degradation-resistant cyclin E frequently caused dysplasia and multiple lung adenocarcinomas. Thus, recapitulation of aberrant cyclin E expression as seen in human premalignant and malignant lung lesions reproduces in the mouse frequent features of lung carcinogenesis, including CIN, Shh pathway activation, dysplasia, single or multiple lung cancers, or presence of metastases. This article reports unique mouse lung cancer models that replicate many carcinogenic changes found in patients. These models provide insights into the carcinogenesis process and implicate cyclin E as a therapeutic target in the lung.lung carcinogenesis ͉ lung cancer ͉ sonic hedgehog C yclin E binds to and activates cyclin-dependent kinase 2 (Cdk2) and promotes G 1 cell cycle transition (1, 2). Cyclin E overexpression shortens the G 1 cell cycle, alters S-phase progression, and causes chromosomal instability (CIN) (3,4). Cyclin E has oncogenic potential. Transgenic cyclin E expression in the mammary gland causes hyperplasia and carcinoma (5). Aberrant cyclin E expression occurs in premalignant lung lesions (6). Cyclin E expression has a negative prognostic impact in lung cancers (7-9). Tobacco carcinogens can transform immortalized human bronchial epithelial (HBE) cells and augment cyclin E expression (10). All-trans-retinoic acid (RA) chemoprevention represses cyclin E and associated Cdk2 kinase activity, causing G 1 arrest (10). This would permit repair of genomic DNA damage by carcinogens and was proposed as a chemoprevention mechanism (10, 11).Regulation of cyclin E is critical for cell cycle progression. Cyclin E accumulates late in G 1 and declines through S phase (1, 2). Cyclin E is regulated by the ubiquitin-proteasome pathway (12). The ubiquitin ligase Cullin 3 promotes ubiquitination of free cyclin E not bound to Cdk2 (13). Ubiquitination of Cdk2-bound cyclin E depends on phosphorylation of threonines Thr-62 and -380 as well as Ser-372 and -384 (14-16). Phosphorylation of these residues allows cyclin E to be recognized by Fbw7 (hCdc4) (15, 17, 18), a phosphoepitope-specific substrate recognition component of the Skp1-Cullin1 F-box protein (SCF) ubiquitin ligase. Fbw7 mutations occur in malignancies and contribute to cell cycle deregulation (15,(18)(19)(20)(21). Mutations of ...

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“…For instance, DNA damage causes specific degradation of cyclin D1, but not cyclin D2 or D3 (Agami and Bernards, 2000). Moreover, although retinoic acid upregulates the expression of cyclin D2, it downregulates expression of cyclin D1 in a manner dependent on Thr286 and GSK3b or that of D3 in a manner independent of Thr283 and GSK3b (Ma et al, 2005). In this regard, it is also notable that the role of GSK3b in phosphorylation of cyclin D1 or D3 has recently been challenged (Casanovas et al, 2004;Okabe et al, 2006;Yang et al, 2006).…”

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confidence: 99%

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

et al. 2007

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Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes cyclin D2 by inhibition of glycogen synthase kinase-3b (GSK3b) through Janus kinase2-dependent activation of phosphatidylinositol 3 0 -kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of cyclin D2, which was mediated by activation of p38. GSK3b and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of cyclin D2 in primary leukemic or myeloma cells. These results indicate that cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3b or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.

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Retinoid Targeting of Different D-Type Cyclins through Distinct Chemopreventive Mechanisms

Cited by 32 publications

References 31 publications

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

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