CDK6 Antagonizes p53-Induced Responses during Tumorigenesis

Bellutti, Florian; Tigan, Anca-Sarmiza; Nebenfuehr, Sofie; Dolezal, Marlies; Zojer, Markus; Grausenburger, Reinhard; Hartenberger, Svenja; Kollmann, Sebastian; Doma, Eszter; Prchal-Murphy, Michaela; Uras, Iris Z.; Höllein, Alexander; Neuberg, Donna; Ebert, Benjamin L.; Ringler, Anna; Mueller, André C.; Loizou, Joanna I.; Hinds, Philip W.; Vogl, Claus; Heller, Gerwin; Kubicek, Stefan; Zuber, Johannes; Malumbres, Marcos; Farlik, Matthias; Villunger, Andreas; Kollmann, Karoline; Sexl, Veronika

doi:10.1158/2159-8290.cd-17-0912

Cited by 62 publications

(80 citation statements)

References 54 publications

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“…The results indicated that the expression of oncoprotein TRIM59 positively correlates with Cyclin CDK6 expression in Wang cell line 2 (A549 cells) and Lee Lung (lung adenocarcinoma and squamous cell lung carcinoma tissue) (Figure A,B). As up‐regulation of CDK6 is closely associated with growth and metastasis of different cancers . This prompted us to test whether TRIM59 promoted cancer growth and metastasis by regulating CDK6 expression through ERK signalling pathway.…”

Section: Resultsmentioning

confidence: 99%

“…As up-regulation of CDK6 is closely associated with growth and metastasis of different cancers. 11,[16][17][18] This prompted us to test whether TRIM59 promoted cancer growth and metastasis by regulating CDK6 expression through ERK signalling pathway. This speculation is verified by the observations that CDK6 mRNA and protein expression significantly decreased when TRIM59 is down-regulated by transducing lung cells with TRIM59 shRNA ( Figure 5A).…”

Section: Trim59 Induced Up-regulation Of Cdk6 Expression Is Dependementioning

confidence: 99%

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An TRIM59‐CDK6 axis regulates growth and metastasis of lung cancer

Geng

Liang

Qin

et al. 2018

J Cellular Molecular Medi

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Lung cancer (LC) is a devastating malignancy with no effective treatments, due to its complex genomic profile. Using bioinformatics analysis and immunohistochemical of lung carcinoma tissues, we show that TRIM59 as a critical oncoprotein relating to LC proliferation and metastasis. In this study, high TRIM59 expression was significantly correlated with lymph node metastasis, distant metastasis, and tumour stage. Furthermore, up‐regulation of TRIM59 expression correlated with poorer outcomes in LC patients. Mechanistically, TRIM59 play a key role in promoting LC growth and metastasis through regulation of extracellular‐signal regulated protein kinase (ERK) signalling pathway and epithelial‐to‐mesenchymal transition (EMT)‐markers, as validated by loss‐of‐function studies. In‐depth bioinformatics analysis showed that there is preliminary evidence of co‐expression of TRIM59 and cyclin dependent kinase 6 (CDK6) in LC. Notably, CDK6 expression significantly decreased when TRIM59 was knocked down in the LC cells. In contrast, exogenous up‐regulation of TRIM59 expression also induced significant increases in the expression of CDK6. Moreover, the expression of CDK6 was also inhibited by the ERK signalling inhibitor, U0126. The results of both loss‐ and gain‐of‐function studies showed that TRIM59 could regulate the expression of CDK6. Collectively, these data provide evidence that TRIM59 is involved in lung carcinoma growth and progression possibly through the induction of CDK6 expression and EMT process by activation of ERK pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Trim59 Induced Up-regulation Of Cdk6 Expression Is Dependementioning

confidence: 99%

An TRIM59‐CDK6 axis regulates growth and metastasis of lung cancer

Geng

Liang

Qin

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

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“…Moreover, it was shown that malignant transformation of hematopoietic cells depend on CDK6-mediated repression of p53 activity, and that CDK6 inhibition could reverse this effect 33 . However, the genomic landscape of cancer cells remains highly heterogeneous and unstable, making the demonstration of a direct correlation between p53 activity and irreversible cell cycle arrest in tumors a challenging task.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells

Wang

Brandenburg

Hernandez‐Segura

et al. 2020

Preprint

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Cellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism. Genotoxic agents exert their anti-cancer functions partly by inducing cancer cells into senescence. However, because of systemic administration and lack of specificity, treatment with genotoxic agents is associated with premature senescence of various non-cancerous cells. Therapy-induced normal senescent cells can have profound detrimental protumorigenic and pro-disease functions via activation of a pro-inflammatory secretory phenotype (SASP).Alternative to genotoxic agents, inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i) have recently proven to be potent anti-cancer interventions able to activate a poorly characterized senescence-like state. Here, we demonstrate that establishment of CDK4/6i-induced stable growth arrest is dependent on p53 transcriptional activity. We show that in human cells, mouse tissues and plasma of metastatic breast cancer patients the CDK4/6i-induced senescent program engages only a partial SASP enriched in p53-associated genes (PASP) but without pro-inflammatory and detrimental NF-κB-dependent factors (NASP). Because of the lack of a NASP, CDK4/6i-induced p16 + senescent cells do not exert detrimental and pro-tumorigenic functions in culture and in vivo. Interestingly, short-term treatment of chemotherapy-induced senescent cells with CDK4/6i is sufficient to partially reduce an already established NASP and improve mouse healthspan via p53 activation and NF-κB repression. Our data suggest that short-and long-term treatment with CDK4/6i can modulate senescence-associated phenotypes and restrict the detrimental effects of senescent cells in cancer therapy.

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“…Conversely, some MCPH gene overexpression promotes cancer cell progression, sometimes through the regulation of p53 activity. MCPH12 contributes to tumor formation by inducing a complex transcriptional program to block p53 in hematopoietic cells [132]. Microarray and bioinformatics analyses indicate that the overexpression of the MCPH17 gene in human colon cancer tissue can affect the occurrence of cancer through the p53 signaling pathway [26].…”

Section: Gene Neurogenesis Ref Carcinogenesismentioning

confidence: 99%

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

Zhou

Zhi

et al. 2020

IJMS

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The stem cells of neurogenesis and carcinogenesis share many properties, including proliferative rate, an extensive replicative potential, the potential to generate different cell types of a given tissue, and an ability to independently migrate to a damaged area. This is also evidenced by the common molecular principles regulating key processes associated with cell division and apoptosis. Autosomal recessive primary microcephaly (MCPH) is a neurogenic mitotic disorder that is characterized by decreased brain size and mental retardation. Until now, a total of 25 genes have been identified that are known to be associated with MCPH. The inactivation (yin) of most MCPH genes leads to neurogenesis defects, while the upregulation (yang) of some MCPH genes is associated with different kinds of carcinogenesis. Here, we try to summarize the roles of MCPH genes in these two diseases and explore the underlying mechanisms, which will help us to explore new, attractive approaches to targeting tumor cells that are resistant to the current therapies.

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CDK6 Antagonizes p53-Induced Responses during Tumorigenesis

Cited by 62 publications

References 54 publications

An TRIM59‐CDK6 axis regulates growth and metastasis of lung cancer

An TRIM59‐CDK6 axis regulates growth and metastasis of lung cancer

Pharmacological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

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