Flipping the cyclin D1 switch in mantle cell lymphoma

Hasanali, Zainul; Sharma, Kamal; Epner, Elliot

doi:10.1016/j.beha.2012.03.001

Cited by 13 publications

(11 citation statements)

References 54 publications

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“…CCND1 is a cell‐cycle regulator that is essential for progression through G 1 phase and is a candidate proto‐oncogene. Abnormal expression of this protein has been implicated in the pathogenesis of several human tumor types, such as breast cancer , lymphoma and ovarian cancer . Moreover, targeting CCND1 appears to be feasible in cancer prognostic and therapy .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐503 suppresses proliferation and cell‐cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1

et al. 2013

The FEBS Journal

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MicroRNAs (miRNAs) are post-transcriptional inhibitor regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for the tumor-suppressor miRNA miR-503 in endometrioid endometrial cancer (EEC) cells. The miR-503 expression level gradually decreases across normal endometrial tissues, endometrial tissues with complex atypical hyperplasia, and EEC tissues. A relatively high level of miR-503 in EEC tissues indicates a longer survival time in EEC patients. The expression of a cell cycle-associated oncogene encoding cyclin D1 (CCND1) was inversely correlated with miR-503 expression in EEC tissues and cell lines. CCND1 has a binding sequence of miR-503 within its 3′ untranslated region, and was confirmed to be a direct target of miR-503 by the fluorescent reporter assays. Increasing the miR-503 level in EEC cells suppressed cell viability, colon formation activity and cell-cycle progression, and the inhibited oncogenic phenotypes induced by miR-503 were alleviated by ectopic expression of CCND1 without the untranslated region sequence. Furthermore, in vivo studies also suggested a suppressive effect of miR-503 on EEC cell-derived xenografts. miR-503 increased in cell cycle-arrested EEC cells, and was restored to a normal level in EEC cells after cell cycle re-entry, while CCND1 displayed the opposite expression pattern. Collectively, this study suggested that miR-503 plays a tumor-suppressor role by targeting CCND1. Abnormal suppression of miR-503 leads to an increase in the CCND1 level, which may promote carcinogenesis and progression of EEC.

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Section: Discussionmentioning

confidence: 99%

MicroRNA‐503 suppresses proliferation and cell‐cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1

et al. 2013

The FEBS Journal

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“…P21, for example, interacts with the tumor suppressor, p53, to control cell proliferation. These investigators, however, did not mention evidence that the proteasome regulates the activity of all four of these cell cycle-related gene products; the proteasome controls levels of p21 [120,121], cyclin D [122][123][124], myc [125], and Wee1 [126].…”

Section: Melatonin the Circadian Clock And Cell Cyclementioning

confidence: 99%

Melatonin feedback on clock genes: a theory involving the proteasome

Vriend

Reíter

2014

Journal of Pineal Research

212

159

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The expression of 'clock' genes occurs in all tissues, but especially in the suprachiasmatic nuclei (SCN) of the hypothalamus, groups of neurons in the brain that regulate circadian rhythms. Melatonin is secreted by the pineal gland in a circadian manner as influenced by the SCN. There is also considerable evidence that melatonin, in turn, acts on the SCN directly influencing the circadian 'clock' mechanisms. The most direct route by which melatonin could reach the SCN would be via the cerebrospinal fluid of the third ventricle. Melatonin could also reach the pars tuberalis (PT) of the pituitary, another melatonin-sensitive tissue, via this route. The major 'clock' genes include the period genes, Per1 and Per2, the cryptochrome genes, Cry1 and Cry2, the clock (circadian locomotor output cycles kaput) gene, and the Bmal1 (aryl hydrocarbon receptor nuclear translocator-like) gene. Clock and Bmal1 heterodimers act on E-box components of the promoters of the Per and Cry genes to stimulate transcription. A negative feedback loop between the cryptochrome proteins and the nucleus allows the Cry and Per proteins to regulate their own transcription. A cycle of ubiquitination and deubiquitination controls the levels of CRY protein degraded by the proteasome and, hence, the amount of protein available for feedback. Thus, it provides a post-translational component to the circadian clock mechanism. BMAL1 also stimulates transcription of REV-ERBa and, in turn, is also partially regulated by negative feedback by REV-ERBa. In the 'black widow' model of transcription, proteasomes destroy transcription factors that are needed only for a particular period of time. In the model proposed herein, the interaction of melatonin and the proteasome is required to adjust the SCN clock to changes in the environmental photoperiod. In particular, we predict that melatonin inhibition of the proteasome interferes with negative feedback loops (CRY/PER and REV-ERBa) on Bmal1 transcription genes in both the SCN and PT. Melatonin inhibition of the proteasome would also tend to stabilize BMAL1 protein itself in the SCN, particularly at night when melatonin is naturally elevated. Melatonin inhibition of the proteasome could account for the effects of melatonin on circadian rhythms associated with molecular timing genes. The interaction of melatonin with the proteasome in the hypothalamus also provides a model for explaining the dramatic 'time of day' effect of melatonin injections on reproductive status of seasonal breeders. Finally, the model predicts that a proteasome inhibitor such as bortezomib would modify circadian rhythms in a manner similar to melatonin.

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“…[ 28 , 30 ] Notably, nuclear cyclin D1 retention during the S phase was shown to promote genomic instability, further contributing to the malignant evolution of MCL. [ 38 ] Our finding that TLR1/2 or TLR5 activation impacts on both cyclin D1 and D3 is of pathogenic relevance in the light of data suggesting that MCL is not exclusively addicted to cyclin D1, which is deregulated by chromosomal translocations, but rather to both cyclin D1 and D3. [ 38 ]…”

Section: Discussionmentioning

confidence: 79%

“…[ 38 ] Our finding that TLR1/2 or TLR5 activation impacts on both cyclin D1 and D3 is of pathogenic relevance in the light of data suggesting that MCL is not exclusively addicted to cyclin D1, which is deregulated by chromosomal translocations, but rather to both cyclin D1 and D3. [ 38 ]…”

Section: Discussionmentioning

confidence: 92%

Toll-Like Receptor 1/2 and 5 Ligands Enhance the Expression of Cyclin D1 and D3 and Induce Proliferation in Mantle Cell Lymphoma

et al. 2016

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Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin’s lymphoma with a still undefined etiology. Several lines of evidence are consistent with the possible involvement of peculiar microenvironmental stimuli sustaining tumor cell growth and survival, as the activation of Toll-like receptors (TLR) 4 and 9. However, little is known about the contribution of other TLRs of pathogenic relevance in the development of MCL. This study reports evidence that MCL cell lines and primary MCL cells express different levels of TLR2 and TLR5, and that their triggering is able to further activate the Akt, MAPK, and NF-κB signaling cascades, known to be altered in MCL cells. This leads to the enhancement of cyclin D1 and D3 over-expression, occurring at post-translational level through a mechanism that likely involves the Akt/GSK-3α/β pathway. Interestingly, in primary B cells, TLR1/2 or TLR5 ligands increase protein level of cyclin D1, which is not usually expressed in normal B cells, and cyclin D3 when associated with CD40 ligand (CD40L), IL-4, and anti-human-IgM co-stimulus. Finally, the activation of TLR1/2 and TLR5 results in an increased proliferation of MCL cell lines and, in the presence of co-stimulation with CD40L, IL-4, and anti-human-IgM also of primary MCL cells and normal B lymphocytes. These effects befall together with an enhanced IL-6 production in primary cultures. Overall, our findings suggest that ligands for TLR1/2 or TLR5 may provide critical stimuli able to sustain the growth and the malignant phenotype of MCL cells. Further studies aimed at identifying the natural source of these TLR ligands and their possible pathogenic association with MCL are warranted in order to better understand MCL development, but also to define new therapeutic targets for counteracting the tumor promoting effects of lymphoma microenvironment.

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Flipping the cyclin D1 switch in mantle cell lymphoma

Cited by 13 publications

References 54 publications

MicroRNA‐503 suppresses proliferation and cell‐cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1

MicroRNA‐503 suppresses proliferation and cell‐cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1

Melatonin feedback on clock genes: a theory involving the proteasome

Toll-Like Receptor 1/2 and 5 Ligands Enhance the Expression of Cyclin D1 and D3 and Induce Proliferation in Mantle Cell Lymphoma

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