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CDK6 Antagonizes p53-Induced Responses during Tumorigenesis.

ABSTRACT: Tumor formation is a multistep process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages, the CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate TP53 (encoding p53) to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53 antagonists Prmt5, Ppm1d, and Mdm4 The findings are relevant to human patients: Tumors with low levels of CDK6 have mutations in TP53 significantly more often than expected.Significance: CDK6 acts at the interface of p53 and RB by driving cell-cycle progression and antagonizing stress responses. While sensitizing cells to p53-induced cell death, specific inhibition of CDK6 kinase activity may provoke the outgrowth of p53-mutant clones from premalignant cells. Cancer Discov; 8(7); 884-97. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.

SUBMITTER: Bellutti F

PROVIDER: S-EPMC6031305 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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CDK6 Antagonizes p53-Induced Responses during Tumorigenesis.

Bellutti Florian F Tigan Anca-Sarmiza AS Nebenfuehr Sofie S Dolezal Marlies M Zojer Markus M Grausenburger Reinhard R Hartenberger Svenja S Kollmann Sebastian S Doma Eszter E Prchal-Murphy Michaela M Uras Iris Z IZ Höllein Alexander A Neuberg Donna S DS Ebert Benjamin L BL Ringler Anna A Mueller Andre C AC Loizou Joanna I JI Hinds Philip W PW Vogl Claus C Heller Gerwin G Kubicek Stefan S Zuber Johannes J Malumbres Marcos M Farlik Matthias M Villunger Andreas A Kollmann Karoline K Sexl Veronika V

Cancer discovery 20180613 7

Tumor formation is a multistep process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages, the CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate <i>TP53</i> (encoding p53) to achieve a fully transformed immortalized s ...[more]

PMID: 29899063

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Project description:BackgroundPulpal inflammation is known to be mediated by multiple signaling pathways. However, whether melatonin plays regulatory roles in pulpal inflammation remains unclear. This study aimed at elucidating an in situ expression of melatonin and its receptors in human pulpal tissues, and the contribution of melatonin on the antagonism of lipopolysaccharide (LPS)-infected pulpal fibroblasts.MethodsMelatonin expression in pulpal tissues harvested from healthy teeth was investigated by immunohistochemical staining. Its receptors, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2), were also immunostained in pulpal tissues isolated from healthy teeth and inflamed teeth diagnosed with irreversible pulpitis. Morphometric analysis was subsequently performed. After LPS infection of cultured pulpal fibroblasts, cyclo-oxygenase (COX) and interleukin-1 β (IL-1 β) transcripts were examined by using reverse transcription-polymerase chain reaction (RT-PCR). Analysis of mRNA expression was performed to investigate an antagonism of LPS stimulation by melatonin via COX and IL-1 β induction. Mann-Whitney U test and One-way ANOVA were used for statistical analysis to determine a significance level.ResultsMelatonin was expressed in healthy pulpal tissue within the odontoblastic zone, cell-rich zone, and in the pulpal connective tissue. Furthermore, in health, strong MT1 and MT2 expression was distributed similarly in all 3 pulpal zones. In contrast, during disease, expression of MT2 was reduced in inflamed pulpal tissues (P-value< 0.001), but not MT1 (P-value = 0.559). Co-culturing of melatonin with LPS resulted in the reduction of COX-2 and IL-1 β expression in primary pulpal fibroblasts, indicating that melatonin may play an antagonistic role to LPS infection in pulpal fibroblasts.ConclusionsHuman dental pulp abundantly expressed melatonin and its receptors MT1 and MT2 in the odontoblastic layers and pulpal connective tissue layers. Melatonin exerted antagonistic activity against LPS-mediated COX-2 and IL-1 β induction in pulpal fibroblasts, suggesting its therapeutic potential for pulpal inflammation and a possible role of pulpal melatonin in an immunomodulation via functional melatonin receptors expressed in dental pulp.

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CDK6 Antagonizes p53-Induced Responses during Tumorigenesis.

Publications

CDK6 Antagonizes p53-Induced Responses during Tumorigenesis.

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