SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways

Gubanova, Evgenia; Issaeva, Natalia; Göktürk, Camilla; Djureinovic, Tatjana; Helleday, Thomas

doi:10.4161/cc.26660

Cited by 36 publications

(48 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, our model most likely illustrates one of several pathways that leads to selective toxicity of roscovitine in HPV+ head and neck cancer cells. We recently found that knockdown of an important player in DNA damage response, SMG-1, in cancer cells led to their increased sensitivity to roscovitine [58]; furthermore, expression of SMG-1 was diminished in HPV-positive HNSCCs due to SMG-1 promoter hypermethylation [59] that may contribute to the sensitivity of HPV+ head and neck cancer cells to roscovitine.…”

Section: Discussionmentioning

confidence: 99%

Selective antitumor activity of roscovitine in head and neck cancer

et al. 2016

Self Cite

View full text Add to dashboard Cite

Radiation and chemotherapy that are commonly used to treat human cancers damage cellular DNA. DNA damage appears to be more toxic to cancer cells than normal cells, most likely due to deregulated checkpoint activation and/or deficiency in DNA repair pathways that are characteristics of many tumors. However, unwanted side effects arise as a result of DNA damage to normal cells during the treatment.Here, we show that roscovitine, a cyclin-dependent kinase (CDK) inhibitor that inhibits CDK-1, CDK-2, CDK-5, CDK-7, and CDK-9 due to competitive binding to the ATP site on the kinases, causes significant DNA damage followed by p53-dependent cell death in human papilloma virus (HPV)-positive, but not in HPV-negative, head and neck cancer cells. Since HPV positivity was a molecular marker for increased sensitivity of cells to roscovitine, we reasoned that systemic roscovitine administration would not be toxic to healthy HPV-negative tissue. Indeed, low roscovitine doses significantly inhibited the growth of HPV-associated xenografted tumors in mice without causing any detectable side effects.Given that inhibition of CDKs has been shown to inhibit replication of several viruses, we suggest that roscovitine treatment may represent a selective and safe targeted therapeutic option against HPV-positive head and neck cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective antitumor activity of roscovitine in head and neck cancer

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…We previously showed that the level of SMG1 protein expressed in Smg1 gt/+ mice was sufficient for its roles in DNA damage repair . However, others have shown that combined loss of ATM and SMG1 in cell lines leads to increased basal DNA damage and alterations to DNA repair pathways . To determine whether the combined roles of SMG1 and ATM in DNA repair was recapitulated in vivo , we examined the formation and resolution of γH2AX foci in Atm −/− compared with Atm −/− Smg1 gt/+ murine embryonic fibroblasts (MEFs).…”

Section: Resultsmentioning

confidence: 99%

“…However, SMG1‐deficient animals showed elevated levels of basal inflammation and oxidative damage to tissues prior to development of cancers indicating a potential role for these pathways in enhancing tumourigenesis in this model. SMG1 and ATM have previously been shown to co‐regulate DNA damage responses and p53 signalling . Brumbaugh et al (2004) demonstrated that both enzymes contribute to the phosphorylation of Upf1 and p53 in response to ionizing radiation (IR).…”

Section: Introductionmentioning

confidence: 99%

“…Brumbaugh et al (2004) demonstrated that both enzymes contribute to the phosphorylation of Upf1 and p53 in response to ionizing radiation (IR). Further SMG1 and ATM are both required for maximal activation of the G1/S checkpoint following exposure to ionising radiation or during oxidative stress . SMG1 can also regulate alternative splicing of p53 in response to DNA damage .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress

Luff

James

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated (ATM) are members of the PI3‐kinase like–kinase (PIKK) family of proteins. ATM is a well‐established tumour suppressor. Loss of one or both alleles of ATM results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm−/−Smg1gt/+ mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm−/−Smg1gt/+ mice displayed increased cytokine levels in haematopoietic tissues compared with wild‐type animals indicating the development of low‐level inflammation and a pro‐tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.

show abstract

“…Independent of p53, SMG-1 can phosphorylate cdc25c and thus allow Cdk2 to activate the G1/S checkpoint following IR. [35] In contrast to the protection mediated by SMG-1 following hyperoxia or IR, [11] one study showed that Smg1 inactivation could prolong the lifespan of C. elegans during paraquat exposure independent of NMD but partially dependent on cep1/p53. [24] These studies support multifaceted modes for how SMG-1 may depend on the presence of p53 to regulate and respond to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

SMG-1 kinase attenuates mitochondrial ROS production but not cell respiration deficits during hyperoxia

Resseguie

Brookes

O’Reilly

2017

Experimental Lung Research

View full text Add to dashboard Cite

Purpose Supplemental oxygen (hyperoxia) used to treat individuals in respiratory distress causes cell injury by enhancing the production of toxic reactive oxygen species (ROS) and inhibiting mitochondrial respiration. The suppressor of morphogenesis of genitalia (SMG-1) kinase is activated during hyperoxia and promotes cell survival by phosphorylating the tumor suppressor p53 on serine 15. Here, we investigate whether SMG-1 and p53 blunt this vicious cycle of progressive ROS production and decline in mitochondrial respiration seen during hyperoxia. Materials and Methods Human lung adenocarcinoma A549 and H1299 or colon carcinoma HCT116 cells were depleted of SMG-1, UPF-1, or p53 using RNA interference, and then exposed to room air (21% oxygen) or hyperoxia (95% oxygen). Immunoblotting was used to evaluate protein expression; a Seahorse Bioanalyzer was used to assess cellular respiration; and flow cytometry was used to evaluate fluorescence intensity of cells stained with mitochondrial or redox sensitive dyes. Results Hyperoxia increased mitochondrial and cytoplasmic ROS and suppressed mitochondrial respiration without changing mitochondrial mass or membrane potential. Depletion of SMG-1 or its cofactor, UPF1, significantly enhanced hyperoxia-induced mitochondrial but not cytosolic ROS abundance. They did not affect mitochondrial mass, membrane potential, or hyperoxia-induced deficits in mitochondrial respiration. Genetic depletion of p53 in A549 cells and ablation of the p53 gene in H1299 or HCT116 cells revealed that SMG-1 influences mitochondrial ROS through activation of p53. Conclusions Our findings show that hyperoxia does not promote a vicious cycle of progressive mitochondrial ROS and dysfunction because SMG-1-p53 signaling attenuates production of mitochondrial ROS without preserving respiration. This suggests antioxidant therapies that blunt ROS production during hyperoxia may not suffice to restore cellular respiration.

show abstract

SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways

Cited by 36 publications

References 37 publications

Selective antitumor activity of roscovitine in head and neck cancer

Selective antitumor activity of roscovitine in head and neck cancer

SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress

SMG-1 kinase attenuates mitochondrial ROS production but not cell respiration deficits during hyperoxia

Contact Info

Product

Resources

About