A prognostic signature of defective p53‐dependent G1 checkpoint function in melanoma cell lines

Carson, Craig C.; Omolo, Bernard; Chu, Haitao; Zhou, Yingchun; Sambade, Maria J.; Peters, Eldon C.; Patrick, Tompkins,; Simpson, Dennis A.; Thomas, Nancy E.; Fan, Cheng; Sarasin, Alain; Dessen, Philippe; Shields, Janiel M.; Ibrahim, Joseph G.; Kaufmann, William K.

doi:10.1111/j.1755-148x.2012.01010.x

Cited by 20 publications

(45 citation statements)

References 68 publications

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“…25 To date it has not been established that aberrant cell cycle checkpoints contribute directly to UV-induced carcinogenesis. Although not proven to be cancer drivers, there is evidence that the G 1 and G 2 checkpoints are defective in some melanoma cell lines, [26][27][28] but there is no evidence that the intra-S checkpoint is abrogated in cancers. The prevailing paradigm has been that checkpoints decrease the probability that damaged DNA will be replicated, allowing time for nucleotide excision repair to remove template lesions.…”

Section: Discussionmentioning

confidence: 99%

Is activation of the intra-S checkpoint in human fibroblasts an important factor in protection against UV-induced mutagenesis?

et al. 2013

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Section: Discussionmentioning

confidence: 99%

Is activation of the intra-S checkpoint in human fibroblasts an important factor in protection against UV-induced mutagenesis?

et al. 2013

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“…Cell lines have been tested and authenticated and verified as mycoplasma-free. Normal human melanocytes (NHMs) (Clonetech) were cultured and western blots were performed as described previously (16). …”

Section: Methodsmentioning

confidence: 99%

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

Carson

Moschos

Edmiston

et al. 2015

Clinical Cancer Research

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Purpose Interleukin-2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared to nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. Experimental Design An ITK specific monoclonal antibody was used to probe sections from de-identified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by immunohistochemistry. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. Results ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacological inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0/G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten null/Braf V600E) melanomas. Conclusions We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility.

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“…Mutation data for the 61 melanoma cell lines were assessed by examination of the CCLE project website (36) for each cell line; data for duplicate cell lines were averaged and cell lines without mutation data were excluded from further analysis. We also obtained the normalized data for GSE40047 (38), profiled by Agilent-014850 Whole Human Genome Microarray 4x44K G4112F. Melanoma cell lines or normal melanocyte lines were labeled as Cy5, and reference RNA was labeled as Cy3.…”

Section: Figurementioning

confidence: 99%

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

Schlegel¹,

Sambade²,

Sather³

et al. 2013

J. Clin. Invest.

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Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. IntroductionAlthough early cutaneous melanoma is usually curable with surgery, distant metastatic melanoma is an aggressive cancer with a median overall survival time of less than 1 year. In 2012, over 75,000 new melanoma diagnoses were expected and over 9,000 deaths were projected (1). Advances in the understanding of distinct melanoma subtypes as well as melanoma immunobiology have resulted in 2 FDA-approved therapies for metastatic melanoma in 2011: vemurafenib, an inhibitor of mutant BRAF -an oncogene present in approximately 50% of melanomas -and ipilimumab, a monoclonal antibody that targets CTLA-4 (2-4). Despite these rather impressive developments, the overall clinical benefit is limited to either small subgroups of patients who

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A prognostic signature of defective p53‐dependent G1 checkpoint function in melanoma cell lines

Cited by 20 publications

References 68 publications

Is activation of the intra-S checkpoint in human fibroblasts an important factor in protection against UV-induced mutagenesis?

Is activation of the intra-S checkpoint in human fibroblasts an important factor in protection against UV-induced mutagenesis?

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

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