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The cyclin-dependent kinase inhibitor p16INK4a physically interacts with transcription factor Sp1 and cyclin-dependent kinase 4 to transactivate microRNA-141 and microRNA-146b-5p spontaneously and in response to ultraviolet light-induced DNA damage.

ABSTRACT: p16(INK4a) is a tumor suppressor protein involved in several stress-related cellular responses, including apoptosis. Recent lines of evidence indicate that p16(INK4a) is also a modulator of gene expression. However, the molecular mechanisms underlying this novel function are still obscure. Here, we present clear evidence that p16(INK4a) modulates the levels of various microRNAs, with marked positive effect on miR-141 and miR-146b-5p. This effect is mediated through the formation of the p16-CDK4-Sp1 heterocomplex, which binds to Sp1 consensus-binding motifs present in the promoters of miR-141 and miR-146b-5p, and it enables their transcription. In addition, we have shown that p16(INK4a) interacts with Sp1 through the fourth ankyrin repeat, which is crucial for Sp1 binding to the miR-141 and miR-146b-5p promoters and their transcriptional activation. The physiological importance of this association was revealed by the inability of cancer-related p16(INK4a) mutants to interact with Sp1. Moreover, we have shown p16-CDK4-Sp1-dependent up-regulation of miR-141 and miR-146b-5p following UV light-induced DNA damage and the role of these two microRNAs in mediating p16-related induction of apoptosis in response to this genotoxic stress. Together, these results indicate that p16(INK4a) associates with CDK4 not only to inhibit the cell cycle but also to enable the transcription of two important onco-microRNAs, which act as downstream effectors.

SUBMITTER: Al-Khalaf HH

PROVIDER: S-EPMC3853297 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The cyclin-dependent kinase inhibitor p16INK4a physically interacts with transcription factor Sp1 and cyclin-dependent kinase 4 to transactivate microRNA-141 and microRNA-146b-5p spontaneously and in response to ultraviolet light-induced DNA damage.

Al-Khalaf Huda H HH Mohideen Peer P Nallar Shreeram C SC Kalvakolanu Dhananjaya V DV Aboussekhra Abdelilah A

The Journal of biological chemistry 20131027 49

p16(INK4a) is a tumor suppressor protein involved in several stress-related cellular responses, including apoptosis. Recent lines of evidence indicate that p16(INK4a) is also a modulator of gene expression. However, the molecular mechanisms underlying this novel function are still obscure. Here, we present clear evidence that p16(INK4a) modulates the levels of various microRNAs, with marked positive effect on miR-141 and miR-146b-5p. This effect is mediated through the formation of the p16-CDK4- ...[more]

PMID: 24163379

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Project description:BackgroundIncreasing evidence has suggested that dysregulation of microRNAs (miRNAs) could contribute to human disease including cancer. Previous miRNA microarray analysis illustrated that miR-320c is down-regulated in various cancers. However, the roles of miR-320c in human bladder cancer have not been well elucidated. Therefore, this study was performed to investigate the biological functions and molecular mechanisms of miR-320c in human bladder cancer cell lines, discussing whether it could be a therapeutic biomarker of bladder cancer in the future.MethodsTwo human bladder cancer cell lines and samples from thirteen patients with bladder cancer were analyzed for the expression of miR-320c by quantitative RT-PCR. Over-expression of miR-320c was established by transfecting mimics into T24 and UM-UC-3. Cell proliferation and cell cycle were assessed by cell viability assay, flow cytometry and colony formation assay. Cell motility ability was evaluated by transwell assay. The target gene of miR-320c was determined by luciferase assay, quantitative RT-PCR and western blot. The regulation of cell cycle and mobility by miR-320c was analyzed by western blot.ResultsWe observed that miR-320c was down-regulated in human bladder cancer tissues and bladder cancer cell lines T24 and UM-UC-3. Over-expression of miR-320c could induce G1 phase arrest in UM-UC-3 and T24 cells, and subsequently inhibited cell growth. We also indentified miR-320c could impair UM-UC-3 and T24 cell motility. In addition, we identified CDK6, a cell cycle regulator, as a novel target of miR-320c. Moreover, we demonstrated miR-320c could induce bladder cancer cell cycle arrest and mobility via regulating CDK6. We also observed that inhibition of miR-320c or restoration of CDK6 in miR-320c-over-expressed bladder cancer cells partly reversed the suppressive effects of miR-320c.ConclusionsmiR-320c could inhibit the proliferation, migration and invasion of bladder cancer cells via regulating CDK6. Our study revealed that miR-320c could be a therapeutic biomarker of bladder cancer in the future.

Dataset Information

The cyclin-dependent kinase inhibitor p16INK4a physically interacts with transcription factor Sp1 and cyclin-dependent kinase 4 to transactivate microRNA-141 and microRNA-146b-5p spontaneously and in response to ultraviolet light-induced DNA damage.

Publications

The cyclin-dependent kinase inhibitor p16INK4a physically interacts with transcription factor Sp1 and cyclin-dependent kinase 4 to transactivate microRNA-141 and microRNA-146b-5p spontaneously and in response to ultraviolet light-induced DNA damage.

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