Cold Spring Harbor Laboratory

About: Cold Spring Harbor Laboratory is a nonprofit organization based out in Cold Spring Harbor, New York, United States. It is known for research contribution in the topics: Gene & Genome. The organization has 3772 authors who have published 6603 publications receiving 1010873 citations. The organization is also known as: CSHL.

bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis

Abstract: Inactivation of p53-dependent apoptosis promotes oncogenic transformation, tumor development, and resistance to many cytotoxic anticancer agents. p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis. To determine whether bax is required for p53-dependent apoptosis, the effects of bax deficiency were examined in primary fibroblasts expressing the E1A oncogene, a setting where apoptosis is dependent on endogenous p53. We demonstrate that bax can function as an effector of p53 in chemotherapy-induced apoptosis and contributes to a p53 pathway to suppress oncogenic transformation. Furthermore, we show that additional p53 effectors participate in these processes. These p53-controlled factors act synergistically with Bax to promote a full apoptotic response, and their action is suppressed by the Bcl-2 and E1B 19K oncoproteins. These studies demonstrate that Bax is a determinant of p53-dependent chemosensitivity and illustrate how p53 can promote apoptosis by coordinating the activities of multiple effectors.

ASYMMETRIC LEAVES1 reveals knox gene redundancy in Arabidopsis

Abstract: The shoot apical meristem comprises undifferentiated stem cells and their derivatives, which include founder cells for lateral organs such as leaves. Meristem maintenance and lateral organ specification are regulated in part by negative interactions between the myb domain transcription factor ASYMMETRIC LEAVES1, which is expressed in lateral organ primordia, and homeobox transcription factors which are expressed in the shoot apical meristem (knox genes). The knox gene SHOOT MERISTEMLESS (STM) negatively regulates ASYMMETRIC LEAVES1 (AS1) which, in turn, negatively regulates other knox genes including KNAT1 and KNAT2, and positively regulates the novel gene LATERAL ORGAN BOUNDARIES (LOB). Genetic interactions with a second gene, ASYMMETRIC LEAVES2 (AS2), indicate it acts at the same position in this hierarchy as AS1. We have used a second-site suppressor screen to isolate mutations in KNAT1 and we show that KNAT1 is partially redundant with STM in regulating stem cell function. Mutations in KNAT2 show no such interaction. We discuss the regulation and evolution of redundancy among knox genes.

Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials

Abstract: Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that-contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors-the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.

Piercing the dark matter: bioinformatics of long-range sequencing and mapping

Abstract: Several new genomics technologies have become available that offer long-read sequencing or long-range mapping with higher throughput and higher resolution analysis than ever before. These long-range technologies are rapidly advancing the field with improved reference genomes, more comprehensive variant identification and more complete views of transcriptomes and epigenomes. However, they also require new bioinformatics approaches to take full advantage of their unique characteristics while overcoming their complex errors and modalities. Here, we discuss several of the most important applications of the new technologies, focusing on both the currently available bioinformatics tools and opportunities for future research.

FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Abstract: Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.