Anti-RBL1 (full length) polyclonal antibody

Objective The pathogenetic underpinnings of extrapulmonary small cell carcinomas (EPSCCs) of the head and neck are poorly understood. We sought to describe the clinical case and whole-exome DNA sequencing data of a patient with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma (SCC). Study Design Case report and whole-exome sequencing of tumor DNA. Setting Academic medical center. Subjects and Methods A 52-year-old man with sinonasal Schneiderian carcinoma in situ whose tumor progressed to small cell carcinoma. We performed whole-exome genetic sequencing and copy-number variation (CNV) analysis of tumor and normal DNA extracted from flash-frozen, paraffin-embedded (FFPE) samples. Results A total of 93 high-confidence, nonsynonymous somatic mutation events were identified in sinonasal SCC, including loss-of-function mutations in TP53, MAML3, a transcriptional coactivator of the Notch pathway, and GAS6, an activating ligand of the TAM family of tyrosine kinase receptors. Focal amplifications of chromosomal regions 6p25-11.1, containing SOX4 and VEGFA, and 14q32.1-32.3, containing AKT1 and the Notch inhibitory ligand DLK1, were also seen. Further CNV analysis revealed deletions in the critical cell cycle regulators CDKN2A, RB1, RBL1, and RBL2 and the chromatin modifier EP300. Conclusions Small cell carcinoma may rarely arise from sinonasal Schneiderian carcinoma in situ and exhibits similar genomic aberrations (eg, SOX amplification, Notch pathway inactivation) to pulmonary small cell carcinoma.

Rapid self-renewal of human embryonic stem (ES) cells (NIH designation WA01 and WA09) is accommodated by an abbreviated cell cycle clue to a reduction in the G1 phase. Thus, molecular mechanisms operative in ES cells may expedite the cellular commitment to progress into S phase to initiate replication of DNA and biosynthesis of histone proteins to form new chromatin. Here we show that the selective cell cycle regulated expression of individual histone H4 gene copies, which is typical for somatic cell types, is already firmly established in human ES cells. This early establishment of H4 gene regulation, which is E2F independent, is consistent with co-expression of the cognate transcriptional regulators HiNF-P and p220(NPAT), Human ES cells differ from somatic cells in the expression of members of the E2F family and RB-related pocket proteins (p105(RB1), p107(RBL1), and P130(RBL2/RB2)) that control expression of genes encoding enzymes for nucleotide metabolism and DNA synthesis. Human ES cells rapidly and robustly (> 200-fold) induce the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) upon gamma-irradiation. This DNA damage response promptly reduces histone gene expression as well as mRNA levels for HiNF-P and p22pNPAT and causes accumulation of unprocessed histone H4 precursor RNAs. Furthermore, while E2F4, E2F5 and p130(RBL2/RB2) are the major E2F and pocket protein mRNAs in actively proliferating ES cells, expression levels of E2F5, E2F6, and p105(RB1) are most strongly elevated during cell cycle arrest in cells responding to DNA damage. Our data suggest that the brief G1 phase of ES cells is supported by a potent p21(WAF1/CIPI) related DNA damage response that functions through several mechanisms to rapidly inhibit cell cycle progression. This response may alter the E2F/pocket protein combinations that control E2F dependent genes and block H4 gene expression by inhibiting histone-specific transcription factors and processing of histone gene transcripts, as well as by destabilizing histone mRNAs. J. Cell. Physiol. 210: 517-526, 2007. (c) 2006 wiley-Liss, Inc.