Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have performed a homozygous deletion screen on 268 candidate genes in 90 human tumor cell lines derived from multiple types of cancers. Most of the candidate genes investigated have been proposed to be involved in cellular processes that are germane to cancer progression, such as cell cycle control, genome maintenance, chromatin remodeling, cell adhesion, and apoptosis. We have detected novel homozygous deletions affecting four independent loci: Brahma-related gene (SMARCA4) on chromosome 19p in the TSU-Pr1 prostate and A427 lung carcinoma lines, Map Kinase Kinase 3 (MAP2K3) on 17q in the NCI-H774 lung tumor cell line, TMPRSS2 on 21q in the Bx PC-3 pancreatic carcinoma line, and Cadherin 6 (CDH6) on 5p in the SK-LU-1 lung carcinoma line. Subsequent analyses of the coding sequences of these four genes using cDNAs from a panel of tumor cell lines revealed multiple sequence variants. The results of this mutation study serve to demonstrate the feasibility of performing high-throughput screens of candidate genes in tumor cell lines to identify genes that may be targeted for mutation during the development of cancer.
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PMID:Mutation analyses of 268 candidate genes in human tumor cell lines. 1141 63

Mitogen-activated protein kinase kinase 3 (MAP2K3) is a member of the dual specificity kinase group. Growing evidence links MAP2K3 to invasion and tumor progression. Here, we identify MAP2K3 as a transcriptional target of endogenous gain-of-function p53 mutants R273H, R175H, and R280K. We show that MAP2K3 modulation occurred at the mRNA and protein levels and that endogenous mutant p53 proteins are capable of binding to and activate the MAP2K3 promoter. In addition, we found that the studied p53 mutants regulate MAP2K3 gene expression through the involvement of the transcriptional cofactors NF-Y and NF-kappaB. Finally, functional studies showed that endogenous MAP2K3 knockdown inhibits proliferation and survival of human tumor cells, whereas the ectopic expression of MAP2K3 can rescue the proliferative defect induced by mutant p53 knockdown. Taken together, our findings define a novel player through which mutant p53 exerts its gain-of-function activity in cancer cells.
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PMID:Mutant p53-induced up-regulation of mitogen-activated protein kinase kinase 3 contributes to gain of function. 2022 20

Mitogen-activated protein kinase kinase 3 (MAP2K3, MKK3) is a member of the dual specificity protein kinase group that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic or stress-inducing stimuli and participates in the MAP kinase-mediated signaling cascade, leading to cell proliferation and survival. Several studies highlighted a critical role for MKK3 in tumor progression and invasion, and we previously identified MKK3 as transcriptional target of mutant (mut) p53 to sustain cell proliferation and survival, thus rendering MKK3 a promising target for anticancer therapies. Here, we found that targeting MKK3 with RNA interference, in both wild-type (wt) and mutp53-carrying cells, induced endoplasmic reticulum stress and autophagy that, respectively, contributed to stabilize wtp53 and degrade mutp53. MKK3 depletion reduced cancer cell proliferation and viability, whereas no significant effects were observed in normal cellular context. Noteworthy, MKK3 depletion in combination with chemotherapeutic agents increased tumor cell response to the drugs, in both wtp53 and mutp53 cancer cells, as demonstrated by enhanced poly (ADP-ribose) polymerase cleavage and reduced clonogenic ability in vitro. In addition, MKK3 depletion reduced tumor growth and improved biological response to chemotherapeutic in vivo. The overall results indicate MKK3 as a novel promising molecular target for the development of more efficient anticancer treatments in both wtp53- and mutp53-carrying tumors.
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PMID:Targeting MKK3 as a novel anticancer strategy: molecular mechanisms and therapeutical implications. 2563 90