Cyclin D1, p16, and retinoblastoma gene regulate mitogenic signaling of endothelin in rat mesangial cells

The retinoblastoma gene product (pRB) participates in the regulation of the cell division cycle through complex formation with numerous cellular regulatory proteins including the potentially oncogenic cyclin D1. Extending the current view of the emerging functional interplay between pRB and D-type cyclins, we now report that cyclin D1 expression is positively regulated by pRB. Cyclin D1 mRNA and protein is specifically downregulated in cells expressing SV40 large T antigen, adenovirus E1A, and papillomavirus E7/E6 oncogene products and this effect requires intact RB-binding, CR2 domain of E1A. Exceptionally low expression of cyclin D1 is also seen in genetically RB-deficient cell lines, in which ectopically expressed wild-type pRB results in specific induction of this G1 cyclin. At the functional level, antibody-mediated cyclin D1 knockout experiments demonstrate that the cyclin D1 protein, normally required for G1 progression, is dispensable for passage through the cell cycle in cell lines whose pRB is inactivated through complex formation with T antigen, E1A, or E7 oncoproteins as well as in cells which have suffered loss-of-function mutations of the RB gene. The requirement for cyclin D1 function is not regained upon experimental elevation of cyclin D1 expression in cells with mutant RB, while reintroduction of wild-type RB into RB-deficient cells leads to restoration of the cyclin D1 checkpoint. These results strongly suggest that pRB serves as a major target of cyclin D1 whose cell cycle regulatory function becomes dispensable in cells lacking functional RB. Based on available data including this study, we propose a model for an autoregulatory feedback loop mechanism that regulates both the expression of the cyclin D1 gene and the activity of pRB, thereby contributing to a G1 phase checkpoint control in cycling mammalian cells.

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Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

Cell Reports ◽

10.1016/j.celrep.2020.108151 ◽

2020 ◽

Vol 32 (11) ◽

pp. 108151

Author(s):

Ke Chen ◽

Xuanmao Jiao ◽

Agnese Di Rocco ◽

Duanwen Shen ◽

Shaohua Xu ◽

...

Keyword(s):

Cyclin D1 ◽

Mitogenic Signaling

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A positive feedback loop involving Erk5 and Akt turns on mesangial cell proliferation in response to PDGF

AJP Cell Physiology ◽

10.1152/ajpcell.00387.2013 ◽

2014 ◽

Vol 306 (11) ◽

pp. C1089-C1100 ◽

Cited By ~ 18

Author(s):

Amit Bera ◽

Falguni Das ◽

Nandini Ghosh-Choudhury ◽

Xiaonan Li ◽

Sanjay Pal ◽

...

Keyword(s):

Cell Proliferation ◽

Dna Synthesis ◽

Cyclin D1 ◽

Positive Feedback ◽

Mesangial Cell ◽

Mesangial Cells ◽

Pi3 Kinase ◽

Dominant Negative ◽

Mesangial Cell Proliferation

Platelet-derived growth factor BB and its receptor (PDGFRβ) play a pivotal role in the development of renal glomerular mesangial cells. Their roles in increased mesangial cell proliferation during mesangioproliferative glomerulonephritis have long been noted, but the operating logic of signaling mechanisms regulating these changes remains poorly understood. We examined the role of a recently identified MAPK, Erk5, in this process. PDGF increased the activating phosphorylation of Erk5 and tyrosine phosphorylation of proteins in a time-dependent manner. A pharmacologic inhibitor of Erk5, XMD8-92, abrogated PDGF-induced DNA synthesis and mesangial cell proliferation. Similarly, expression of dominant negative Erk5 or siRNAs against Erk5 blocked PDGF-stimulated DNA synthesis and proliferation. Inhibition of Erk5 attenuated expression of cyclin D1 mRNA and protein, resulting in suppression of CDK4-mediated phosphorylation of the tumor suppressor protein pRb. Expression of cyclin D1 or CDK4 prevented the dominant negative Erk5- or siErk5-mediated inhibition of DNA synthesis and mesangial cell proliferation induced by PDGF. We have previously shown that phosphatidylinositol 3-kinase (PI3-kinase) contributes to PDGF-induced proliferation of mesangial cells. Inhibition of PI3-kinase blocked PDGF-induced phosphorylation of Erk5. Since PI3-kinase acts through Akt, we determined the role of Erk5 on Akt phosphorylation. XMD8-92, dominant negative Erk5, and siErk5 inhibited phosphorylation of Akt by PDGF. Interestingly, we found inhibition of PDGF-induced Erk5 phosphorylation by a pharmacological inhibitor of Akt kinase and kinase dead Akt in mesangial cells. Thus our data unfold the presence of a positive feedback microcircuit between Erk5 and Akt downstream of PI3-kinase nodal point for PDGF-induced mesangial cell proliferation.

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Inverse Association Between Cyclin D1 Overexpression and Retinoblastoma Gene Mutation in Thyroid Carcinomas

Endocrine ◽

10.1385/endo:8:1:61 ◽

1998 ◽

Vol 8 (1) ◽

pp. 61-64 ◽

Cited By ~ 29

Author(s):

Minjing Zou ◽

Yufei Shi ◽

Nadir R. Farid ◽

Sultan T. Al-Sedairy

Keyword(s):

Cyclin D1 ◽

Gene Mutation ◽

Inverse Association ◽

Retinoblastoma Gene ◽

Thyroid Carcinomas

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The PTEN/PI3K/Akt signaling pathway mediates HMGB1-induced cell proliferation by regulating the NF-κB/cyclin D1 pathway in mouse mesangial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00385.2013 ◽

2014 ◽

Vol 306 (12) ◽

pp. C1119-C1128 ◽

Cited By ~ 24

Author(s):

Xiao-Juan Feng ◽

Shu-Xia Liu ◽

Chao Wu ◽

Peng-Peng Kang ◽

Qing-Juan Liu ◽

...

Keyword(s):

Cyclin D1 ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Mesangial Cells ◽

High Mobility ◽

Nuclear Factor Κb ◽

Pyrrolidine Dithiocarbamate ◽

Chromosomal Protein ◽

Dependent Manner ◽

Concentration Dependent Manner

Our previous experiment confirmed that high-mobility group box chromosomal protein 1 (HMGB1) was involved in the pathogenesis of Lupus nephritis (LN) by upregulating the proliferation of the mouse mesangial cell line (MMC) through the cyclin D1/CDK4/p16 system, but the precise mechanism is still unknown. Therefore, in the present study, we demonstrated that HMGB1 induced the proliferation of MMC cells in a time- and concentration-dependent manner, downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression, increased the level of Akt serine 473 phosphorylation, and induced p65 subunit nuclear translocation. The overexpression of PTEN prevented the upregulation of HMGB1-induced proliferation by blocking the activation of Akt. The knockdown of Akt by siRNA technology and blocking the nuclear factor-κB (NF-κB) pathway using pyrrolidine dithiocarbamate (PDTC) and SN50, inhibitors of NF-κB, both attenuated the HMGB1-induced proliferation by counteracting the activation of the cyclin D1. In addition, while sh-Akt partly blocked the nuclear translocation of the p65 subunit, PDTC did not affect the activation of the Akt induced by HMGB1 in MMC cells. These findings indicate that HMGB1 induced the proliferation of MMC cells by activating the PTEN/phosphoinositide-3-kinase (PI3K)/Akt/NF-κB signaling pathway.

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1001 Apoptosis, proliferation and P53, cyclin D1 and retinoblastoma gene expression in relation to radiation response in muscle-invasive bladder cancer

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/s0360-3016(99)90227-4 ◽

1999 ◽

Vol 45 (3) ◽

pp. 257-258

Author(s):

L. Moonen ◽

M. Gallee ◽

M. Verheij ◽

F. Ong ◽

S. Horenblas ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Cyclin D1 ◽

Radiation Response ◽

Invasive Bladder Cancer ◽

Retinoblastoma Gene ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

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Overexpression of protein kinase G using adenovirus inhibits cyclin E transcription and mesangial cell cycle

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.5.f851 ◽

2001 ◽

Vol 280 (5) ◽

pp. F851-F859 ◽

Cited By ~ 9

Author(s):

Satoko Hanada ◽

Yoshio Terada ◽

Seiji Inoshita ◽

Sei Sasaki ◽

Suzanne M. Lohmann ◽

...

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Cyclin D1 ◽

Natriuretic Peptide ◽

Promoter Activity ◽

Mesangial Cell ◽

Mesangial Cells ◽

Cyclin E ◽

Cyclin A ◽

Protein Kinase G

The cGMP-cGMP-dependent protein kinase (protein kinase G) system plays an important role in the pathogenesis of mesangial proliferative glomerulonephritis. However, the molecular mechanisms of the inhibitory effects of the cGMP-protein kinase G system in the cell cycle progression of mesangial cells are not well known. To determine the inhibitory pathway of cGMP-protein kinase G in cultured mesangial cells, we investigated the effects of cGMP- and adenovirus-mediated overexpression of protein kinase G on the promoter activities of cyclin E, cyclin D1, and cyclin A. 8-Bromo-cGMP (8-BrcGMP) and overexpression of protein kinase G reduced [3H]thymidine uptake, reduced the numbers of cells in S and G2/M phases, and decreased the phosphorylation of retinoblastoma (Rb) protein. 8-BrcGMP (10−3 M), protein kinase G adenovirus (Ad-cGKIβ; 1010 plaque-forming units/ml), atrial natriuretic peptide (ANP), and C-type natriuretic peptide (CNP) inhibited the promoter activity of cyclin E to 49, 57, 77, and 78%, respectively. On the other hand, the promoter activities of cyclin D1 and cyclin A were not changed significantly. In Western blot analysis, 8-BrcGMP, Ad-cGKIβ, ANP, and CNP also inhibited cyclin E protein expression dose and time dependently. The p44/p42 mitogen-activated protein kinase (MAPK) kinase 1-p44/p42 MAPK had no effect on cyclin E promoter activities, and the cGMP-protein kinase G pathway did not change MAPK activity. In conclusion, our findings suggest that the reduction of the cyclin E promoter activity that downregulates G1/S transition plays a dominant role in the cGMP- and protein kinase G-induced inhibition of mesangial cell proliferation.

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