Tumor suppressor p16INK4a inhibits cancer cell growth by down-regulating eEF1A2 through a direct interaction

Lee, Mee-Hyun; Choi, Bu Young; Cho, Yong‐Yeon; Lee, Sung Young; Huang, Zunnan; Kundu, Joydeb Kumar; Kim, Myoung Ok; Kim, Dong Joon; Bode, Ann M.; Surh, Young Joon; Dong, Zigang

doi:10.1242/jcs.113613

Cited by 29 publications

(28 citation statements)

References 49 publications

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“…Although eEF2K was not identified in our screen, eEF2 was identified as an interacting protein of CIS-derived candidate gene, Cdkn2a, as was eukaryotic translation initiation factor 1β (EIF1B), whereas eukaryotic translation elongation factor 1α (EEF1A2) was identified in our network as an interacting partner of Map3k1. Interestingly, EE1A2 has only recently been reported as an interacting partner of CDKN2A (46), establishing another link between this CIS-derived candidate gene and translation elongation. Given the accelerated MB tumorigenesis noted in both this study and the previously published SB screen (15), these data strongly implicate translation elongation in this process.…”

Section: −20mentioning

confidence: 99%

Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups

Genovesi

Davis

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The Sleeping Beauty (SB) transposon mutagenesis screen is a powerful tool to facilitate the discovery of cancer genes that drive tumorigenesis in mouse models. In this study, we sought to identify genes that functionally cooperate with sonic hedgehog signaling to initiate medulloblastoma (MB), a tumor of the cerebellum. By combining SB mutagenesis with Patched1 heterozygous mice (Ptch1 lacZ/+ ), we observed an increased frequency of MB and decreased tumor-free survival compared with Ptch1 lacZ/+ controls. From an analysis of 85 tumors, we identified 77 common insertion sites that map to 56 genes potentially driving increased tumorigenesis. The common insertion site genes identified in the mutagenesis screen were mapped to human orthologs, which were used to select probes and corresponding expression data from an independent set of previously described human MB samples, and surprisingly were capable of accurately clustering known molecular subgroups of MB, thereby defining common regulatory networks underlying all forms of MB irrespective of subgroup. We performed a network analysis to discover the likely mechanisms of action of subnetworks and used an in vivo model to confirm a role for a highly ranked candidate gene, Nfia, in promoting MB formation. Our analysis implicates candidate cancer genes in the deregulation of apoptosis and translational elongation, and reveals a strong signature of transcriptional regulation that will have broad impact on expression programs in MB. These networks provide functional insights into the complex biology of human MB and identify potential avenues for intervention common to all clinical subgroups.

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Section: −20mentioning

confidence: 99%

Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups

Genovesi

Davis

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…These results are similar to the additive effects of EGCG and TSA on NF-κB activity and cell invasion as previously reported (19). These effects may be mediated at least in part through increased p16 INK4a expression, which inhibits cancer cell proliferation and induces cellular senescence (4,5). Reduced p16 INK4a expression may result in sustained binding of CDK4/CDK6 to cyclin D and subsequent phosphorylation of Rb protein, resulting in uncontrolled cell proliferation (2,3).…”

Section: Discussionmentioning

confidence: 99%

“…Reduced p16 INK4a expression may result in sustained binding of CDK4/CDK6 to cyclin D and subsequent phosphorylation of Rb protein, resulting in uncontrolled cell proliferation (2,3). p16 INK4a expression may also mediate cell senescence (5,20); it may also inhibit cell growth by directly interacting with the eukaryotic elongation factor 1A2 (eEF1A2), reducing its expression (4). In addition, EGCG-induced apoptosis of Jurkat cells through hydrogen peroxide production has been demonstrated (21).…”

Section: Discussionmentioning

confidence: 99%

“…The p16-cyclin D1-CDK4-Rb pathway regulates cell cycle transition from the G1 to the S phase; point mutations and/or epigenetic modifications in this pathway are observed in almost all human cancers (2,3). In addition to regulating the CDK4-Rb pathway, p16 INK4a decreases eukaryotic elongation factor (eEF) 1A2 expression, reducing cancer cell proliferation (4). It also induces cellular senescence in a cooperative manner with p21 Waf1/Cip1 , which was confirmed in double-knockout mice that were more susceptible to skin tumor formation (5).…”

Section: Introductionmentioning

confidence: 99%

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Epigallocatechin-3-gallate and trichostatin A synergistically inhibit human lymphoma cell proliferation through epigenetic modification of p16INK4a

Shen

et al. 2013

Oncology Reports

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DNA methylation and histone deacetylation play important roles in the occurrence and development of cancers by inactivating the expression of tumor suppressors, including p16(INK4a), a cyclin-dependent kinase inhibitor. The present study investigated the effect of epigallocatechin-3-gallate (EGCG) alone or in combination with trichostatin A (TSA) on p16(INK4a) gene expression and growth in human malignant lymphoma CA46 cells. CA46 cell viability and cell cycle were analyzed; methylation of the p16(INK4a) gene was assessed by nested methylation-specific PCR (n-MSP). p16(INK4a )mRNA and protein expression was determined by real-time quantitative PCR and western blot analyses, respectively. Both EGCG and TSA alone inhibited CA46 cell proliferation; the combined treatment (6 µg/ml EGCG and 15 ng/ml TSA) significantly reduced CA46 cell proliferation from 24 to 96 h (all P<0.001). Cells treated with 24 µg/ml EGCG or the combination treatment (6 µg/ml EGCG and 15 ng/ml TSA) had lower proliferative indices when compared to the other groups. Co-treatment with EGCG and TSA decreased p16(INK4a) gene methylation, which coincided with increased p16(INK4a) mRNA and protein expression. Thus, EGCG and TSA synergistically reactivate p16(INK4a) gene expression in part through reducing promoter methylation, which may decrease CA46 cell proliferation.

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“…Hence, the p16 pathway of action connects the process of oncogenesis and cell aging; downregulation of p16 by hypermethylation, point mutation, or deletion of the gene leads to the progression of cell cycle whereas activation of the gene will stimulate cellular aging or senescence. [789] Inactivation of p16 is well-documented in several malignancies as squamous cell carcinoma of cervix,[10] oropharynx,[11] and esophagus,[12] non-small cell carcinoma of lung,[13] mesothelioma,[14] and pancreatic carcinoma. [15]…”

mentioning

confidence: 99%

p16 protein is upregulated in a stepwise fashion in colorectal adenoma and colorectal carcinoma

Al-Ahwal¹,

Gomaa²,

Emam³

et al. 2016

Saudi J Gastroenterol

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Background/Aims:p16 is tumor suppressor gene acting as a cell cycle regulator. The present study was conducted to compare p16 expression in normal, dysplastic, and malignant colonic mucosae, and to explore its relation to clinicopathological variables and follow-up data in colorectal carcinoma (CRC).Patients and Methods:Tissue microarrays were performed from 25 normal colonic mucosae, 41 colonic adenomas, and 191 CRC, with corresponding 50 nodal metastases. Immunohistochemistry was performed using anti-p16 antibody, sections were scored, and statistical analysis was performed. K-ras mutation detection was also performed.Results:Immunoexpression of p16 was significantly higher in CRC than in adenomas (P = 0.033) and normal colonic mucosa (P = 0.005). There was no statistically significant difference between p16 expression in CRC and nodal metastasis. There was no significant association between p16 immunoexpression in CRC and all clinicopathological data and survival probability. K-ras mutations were detected in 34% of CRC. However, there was no correlation between K-ras status and p16 expression (P = 0.325).Conclusion:Absence of p16 expression is correlated to a benign course of CRC adenomas. p16 has a key role in CRC progression and can be used as a marker for colorectal adenoma. On the other hand, it has no role as a predictive and/or prognostic factor in CRC. Further extended studies are required to explore the role of p16 as indicator of premalignant lesions in the colon and to test its relation with CRC histological grade, as well as to test its value as a new therapeutic target.

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Tumor suppressor p16INK4a inhibits cancer cell growth by down-regulating eEF1A2 through a direct interaction

Cited by 29 publications

References 49 publications

Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups

Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups

Epigallocatechin-3-gallate and trichostatin A synergistically inhibit human lymphoma cell proliferation through epigenetic modification of p16INK4a

p16 protein is upregulated in a stepwise fashion in colorectal adenoma and colorectal carcinoma

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