Nucleolar GTP-binding Protein-1 (NGP-1) Promotes G1 to S Phase Transition by Activating Cyclin-dependent Kinase Inhibitor p21Cip1/Waf1

Datta, Debduti; Kumaraswamy, Anbarasu; Rajabather, Suryaraja; Priya, Rangasamy Sneha; Desai, Pavitra; Mahalingam, Sundarasamy

doi:10.1074/jbc.m115.637280

Cited by 18 publications

(23 citation statements)

References 72 publications

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“…These GTPases are found to be shuttling between nucleolus, nucleus and cytoplasm 5 , 6 . Depletion of GNL2, GNL3 and GNL3L has shown to alter G1/S and G2/M cell cycle transition indicates their role in cell cycle regulation 7 – 9 but the molecular mechanism yet to be defined.…”

Section: Introductionmentioning

confidence: 99%

“…GNL3L and GNL3 (nucleostemin) are localized in the nucleolus and modulate ribosomal as well as non-ribosomal pathways 15 – 21 to promote cell proliferation. Several reports suggest that a functional interaction of GNL family members with large and small ribosomal proteins 7 , 8 , 20 but the functional consequences of these interactions are poorly understood. Studies are warranted to understand whether GNL1 participates in ribosomal biogenesis or has some non-ribosomal functions to regulate cell proliferation during tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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Interplay between human nucleolar GNL1 and RPS20 is critical to modulate cell proliferation

Krishnan

Boddapati

Mahalingam

2018

Sci Rep

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Human Guanine nucleotide binding protein like 1 (GNL1) belongs to HSR1_MMR1 subfamily of nucleolar GTPases. Here, we report for the first time that GNL1 promotes cell cycle and proliferation by inducing hyperphosphorylation of retinoblastoma protein. Using yeast two-hybrid screening, Ribosomal protein S20 (RPS20) was identified as a functional interacting partner of GNL1. Results from GST pull-down and co-immunoprecipitation assays confirmed that interaction between GNL1 and RPS20 was specific. Further, GNL1 induced cell proliferation was altered upon knockdown of RPS20 suggesting its critical role in GNL1 function. Interestingly, cell proliferation was significantly impaired upon expression of RPS20 interaction deficient GNL1 mutant suggest that GNL1 interaction with RPS20 is critical for cell growth. Finally, the inverse correlation of GNL1 and RPS20 expression in primary colon and gastric cancers with patient survival strengthen their critical importance during tumorigenesis. Collectively, our data provided evidence that cross-talk between GNL1 and RPS20 is critical to promote cell proliferation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interplay between human nucleolar GNL1 and RPS20 is critical to modulate cell proliferation

Krishnan

Boddapati

Mahalingam

2018

Sci Rep

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“…NOG2 —a GTPase—is involved in the regulation of G1 to S phase transition (Datta et al 2015) and ribosomal biogenesis (Essers et al 2014). NOG2 induces cell proliferation by increasing TP53 (and its downstream product, CDKN1A/p21) protein levels, and decreasing RPL23A protein levels (Datta et al 2015). Interest in NOG2 arose from the observation that the protein is overexpressed in some cancers, such as breast or colorectal (Racevskis et al 1996).…”

Section: Resultsmentioning

confidence: 99%

“…NOG2 induces P53 activation by inhibiting RPL23A (60S ribosomal protein L23a), a ribosomal protein that triggers p53 degradation via Mdm2. P53 expression leads to the expression of the cyclin-dependent kinase inhibitor p21 (Datta et al 2015), which is required for the formation of the cyclin D1-CDK4 complex. At higher concentrations, p21 inhibits the cyclin D1-CDK4 complex (LaBaer et al 1997).…”

Section: Resultsmentioning

confidence: 99%

Virus-host protein-protein interactions between human papillomavirus 16 E6 A1 and D2/D3 sub-lineages: variances and similarities

Dayer

Lucas

Masoom

et al. 2020

Preprint

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High-risk strains of human papillomavirus are causative agents for cervical and other mucosal cancers with type 16 being the most frequent. Compared to the European Prototype (A1 denoted “EP”), the Asian-American (D2/D3 denoted “AA”) sub-lineage or “variant” was reported to have increased abilities to promote carcinogenesis. Few, if any global interactome studies, have looked at protein-protein interactions (PPIs) between host proteins and variants of the key transforming E6 protein. We applied a primary human foreskin keratinocyte model transduced with EP and AA variant E6 genes and co-immunoprecipitated expressed E6 proteins along with interacting cellular proteins to potentially detect diversity in virus-host relationships. We reasoned that due to single nucleotide polymorphisms, AAE6 and EPE6 may have unique PPIs with host cellular proteins—conferring gain or loss of function—resulting in varied abilities to promote carcinogenesis. Using liquid chromatography-mass spectrometry and stringent interactor selection based on the number of peptides, we identified 25 candidates: 6 unique to AAE6 and EPE6, respectively along with 13 common E6 targets between AAE6 and EPE6. We also applied a more inclusive process based on pathway selection and discovered 171 target proteins: 90 unique AAE6 and 61 unique EPE6 along with 20 common E6 targets between the two sub-lineages. Interpretations for both approaches were made drawing from different databases such as UniProt, BioGRID and Reactome. The detected E6 targets were found to be implicated in deregulating a variety of cellular functions such as DNA replication and repair, energetics and hypoxia, mitogen-activated protein kinases/extracellular signal-regulated kinases signaling, tumour suppression and immune response, as well as pathways hijacked from embryogenesis and wound healing to drive cancer development. Validation experiments such as reverse co-immunoprecipitation and RNA interference are required to substantiate these findings. Here, we provide an unprecedented resource for new research questions and hypotheses testing in HR HPV biology. If variant-specific interactions are verified, their targeted disruption may potentially yield new options for personalized cancer treatment strategies.

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“…MTT assay, RT-qPCR, and Western blotting were performed as described previously (50). Primers used for RT-qPCR are listed in Table S1.…”

Section: Chip-pcrmentioning

confidence: 99%

E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases

Karthik

Desai

Sukumar

et al. 2018

Journal of Biological Chemistry

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RAS proteins are major human oncogenes, and most of the studies are focused on enzymatic RAS effectors. Recently, nonenzymatic RAS effectors (RASSF, RAS association domain family) have garnered special attention because of their tumor-suppressive properties in contrast to the oncogenic potential of the classical enzymatic RAS effectors. Whereas most members of RASSF family are deregulated by promoter hypermethylation, RASSF8 promoter remains unmethylated in many cancers but the mechanism(s) of its down-regulation remains unknown. Here, we unveil E4BP4 as a critical transcriptional modulator repressing RASSF8 expression through histone methyltransferases, G9a and SUV39H1. In line with these observations, we noticed a negative correlation of RASSF8 and E4BP4 expression in primary breast tumor samples. In addition, our data provide evidence that E4BP4 attenuates RASSF8-mediated anti-proliferation and apoptosis, shedding mechanistic insights into RASSF8 down-regulation in breast cancers. Collectively, our study provides a better understanding on the epigenetic regulation of RASSF8 function and implicates the development of better treatment strategies.

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Nucleolar GTP-binding Protein-1 (NGP-1) Promotes G1 to S Phase Transition by Activating Cyclin-dependent Kinase Inhibitor p21Cip1/Waf1

Cited by 18 publications

References 72 publications

Interplay between human nucleolar GNL1 and RPS20 is critical to modulate cell proliferation

Interplay between human nucleolar GNL1 and RPS20 is critical to modulate cell proliferation

Virus-host protein-protein interactions between human papillomavirus 16 E6 A1 and D2/D3 sub-lineages: variances and similarities

E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases

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