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Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways.
Slebos RJ, Jehmlich N, Brown B, Yin Z, Chung CH, Yarbrough WG, Liebler DC
(2013) Int J Cancer 132: 568-79
MeSH Terms: Argininosuccinate Synthase, Cell Differentiation, DNA, Viral, E2F1 Transcription Factor, E2F4 Transcription Factor, Extracellular Matrix, Gene Expression Profiling, Humans, Oropharyngeal Neoplasms, Papillomaviridae, Papillomavirus Infections, Proteomics
Show Abstract · Added March 7, 2014
Oropharyngeal carcinoma (OPC) can be classified into two equally prevalent subtypes depending on the presence of human papillomavirus (HPV). Patients with HPV-positive (HPV+) OPC represent a unique cohort with a distinct tumor biology and clinical behavior compared to HPV-negative (HPV-) OPC. Genetic studies have demonstrated chromosomal and gene expression changes associated with distinct subclasses of OPC; however, the proteomic consequences of HPV infection are not known. We analyzed sets of ten HPV+ and ten HPV- OPCs and ten normal adult oral epithelia using a standardized global proteomic analysis platform. This analysis yielded a total of 2,653 confidently identified proteins from which we chose 31 proteins on the basis of expression differences between HPV+, HPV- and normal epithelium for targeted protein quantitation. Analysis of differentially expressed proteins by HPV status revealed enrichment of proteins involved in epithelial cell development, keratinization and extracellular matrix organization in HPV- OPC, whereas enrichment of proteins in DNA initiation and replication and cell cycle control was found for HPV+ OPC. Enrichment analysis for transcription factor targets identified transcription factors E2F1 and E2F4 to be highly expressed in HPV+ OPC. We also found high expression of argininosuccinate synthase 1 in HPV+ OPC, suggesting that HPV+ OPC is more dependent on conditionally essential amino acid, arginine, and this was confirmed on a OPC-specific tissue microarray. These identified proteomic changes reveal novel driving molecular pathways for HPV+ and HPV- OPCs that may be pertinent in therapeutic strategies and outcomes of OPC.
Copyright © 2012 UICC.
0 Communities
2 Members
0 Resources
12 MeSH Terms
Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells.
Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL
(2002) Mol Cell Biol 22: 8184-98
MeSH Terms: Animals, Antibiotics, Antineoplastic, CDC2-CDC28 Kinases, Carcinoma, Cell Cycle Proteins, Cell Division, Cell Line, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases, Cyclins, DNA-Binding Proteins, E2F4 Transcription Factor, Enzyme Inhibitors, Epithelial Cells, Genes, Reporter, Growth Inhibitors, Humans, Nuclear Proteins, Phosphoproteins, Protein Binding, Protein-Serine-Threonine Kinases, Proteins, Retinoblastoma Protein, Retinoblastoma-Like Protein p107, Retinoblastoma-Like Protein p130, Signal Transduction, Sirolimus, Tacrolimus Binding Proteins, Transcription Factors, Transforming Growth Factor beta, Tumor Suppressor Proteins
Show Abstract · Added February 17, 2014
Transforming growth factor beta (TGF-beta) induces cell cycle arrest of most nontransformed epithelial cell lines. In contrast, many human carcinomas are refractory to the growth-inhibitory effect of TGF-beta. TGF-beta overexpression inhibits tumorigenesis, and abolition of TGF-beta signaling accelerates tumorigenesis, suggesting that TGF-beta acts as a tumor suppressor in mouse models of cancer. A screen to identify agents that potentiate TGF-beta-induced growth arrest demonstrated that the potential anticancer agent rapamycin cooperated with TGF-beta to induce growth arrest in multiple cell lines. Rapamycin also augmented the ability of TGF-beta to inhibit the proliferation of E2F1-, c-Myc-, and (V12)H-Ras-transformed cells, even though these cells were insensitive to TGF-beta-mediated growth arrest in the absence of rapamycin. Rapamycin potentiation of TGF-beta-induced growth arrest could not be explained by increases in TGF-beta receptor levels or rapamycin-induced dissociation of FKBP12 from the TGF-beta type I receptor. Significantly, TGF-beta and rapamycin cooperated to induce growth inhibition of human carcinoma cells that are resistant to TGF-beta-induced growth arrest, and arrest correlated with a suppression of Cdk2 kinase activity. Inhibition of Cdk2 activity was associated with increased binding of p21 and p27 to Cdk2 and decreased phosphorylation of Cdk2 on Thr(160). Increased p21 and p27 binding to Cdk2 was accompanied by decreased p130, p107, and E2F4 binding to Cdk2. Together, these results indicate that rapamycin and TGF-beta cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity.
0 Communities
1 Members
0 Resources
34 MeSH Terms
E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation.
Strom DK, Cleveland JL, Chellappan S, Nip J, Hiebert SW
(1998) Cell Growth Differ 9: 59-69
MeSH Terms: Apoptosis, Carrier Proteins, Cell Cycle, Cell Cycle Proteins, Cell Differentiation, Cell Line, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, E2F2 Transcription Factor, E2F3 Transcription Factor, E2F4 Transcription Factor, E2F5 Transcription Factor, Gene Expression Regulation, Granulocyte Colony-Stimulating Factor, Granulocytes, Humans, Interleukin-3, Retinoblastoma-Binding Protein 1, Transcription Factor DP1, Transcription Factors, Tumor Cells, Cultured
Show Abstract · Added June 10, 2010
Interleukin 3 (IL-3)-dependent 32D.3 myeloid cells are an attractive model system for the analysis of hematopoietic cell growth, differentiation, and apoptosis. In these cells, E2F-3, E2F-4, and DP-1 are regulated by both IL-3 and granulocyte colony-stimulating factor (G-CSF), whereas E2F-1 was expressed at low levels and was not regulated by either cytokine. E2F-2 and E2F-5 were not detectable. To examine phenotypes associated with the loss of normal cell cycle regulation by pRb, we established E2F-1- and E2F-3-overexpressing cell lines. In contrast to E2F-1, E2F-3 overexpression did not accelerate apoptosis or promote S-phase entry in the absence of IL-3, demonstrating that they are not functionally redundant. In addition, when cells were cultured in G-CSF to stimulate granulocytic differentiation, E2F-1 overexpression overrode survival functions provided by G-CSF and serum and induced apoptosis. In contrast, cells overexpressing E2F-3 exhibited normal granulocytic differentiation. Bcl-2 coexpression blocked E2F-1-induced apoptosis in the presence of G-CSF. However, these cells were blocked in the granulocytic differentiation program at the metamyelocyte stage and remained dependent on G-CSF for continuous culture. Cells overexpressing both E2F-1 and Bcl-2 exhibited slowed but continuous cell cycling in the absence of IL-3 until they eventually succumbed to apoptosis. Therefore, E2F-1, but not E2F-3, can temporally replace the requirement for growth factors to promote cell cycle progression, and in terminally differentiating cells, this leads to a block in differentiation and induction of apoptosis.
1 Communities
1 Members
0 Resources
22 MeSH Terms