Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Hedgehog (Hh) signaling pathway is intimately linked to cell growth and differentiation, with normal roles in embryonic pattern formation and adult tissue homeostasis and pathological roles in tumor initiation and growth. Recent advances in our understanding of Hh response have resulted from the identification of new pathway components and new mechanisms of action for old pathway components. The most striking new finding is that signal transmission from membrane to cytoplasm proceeds through recruitment, by the seven-transmembrane protein Smoothened, of an atypical kinesin, which routes pathway activation by interaction with other components of a complex that includes the latent zinc finger transcription factor, Ci.
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PMID:The Hedgehog response network: sensors, switches, and routers. 1520 20

Aneuploidy, an abnormal chromosome number that deviates from a multiple of the haploid, has been recognized as a common feature of cancers for >100 yr. Previously, we showed that the rate of chromosome missegregation/chromosomal instability (CIN) determines the effect of aneuploidy on tumors; whereas low rates of CIN are weakly tumor promoting, higher rates of CIN cause cell death and tumor suppression. However, whether high CIN inhibits tumor initiation or suppresses the growth and progression of already initiated tumors remained unclear. We tested this using the Apc(Min/+) mouse intestinal tumor model, in which effects on tumor initiation versus progression can be discriminated. Apc(Min/+) cells exhibit low CIN, and we generated high CIN by reducing expression of the kinesin-like mitotic motor protein CENP-E. CENP-E(+/-);Apc(Min/+) doubly heterozygous cells had higher rates of chromosome missegregation than singly heterozygous cells, resulting in increased cell death and a substantial reduction in tumor progression compared with Apc(Min/+) animals. Intestinal organoid studies confirmed that high CIN does not inhibit tumor cell initiation but does inhibit subsequent cell growth. These findings support the conclusion that increasing the rate of chromosome missegregation could serve as a successful chemotherapeutic strategy.
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PMID:High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation. 2714 13

Chromosomal instability (CIN) is defined as a high rate of whole chromosome loss or gain and is a hallmark of many aneuploid solid tumors. CIN positively correlates with poor patient prognosis and chemotherapeutic resistance. Despite this clinical importance, the role of CIN in tumor initiation, growth and/or progression remains poorly understood. To date, the only strategies developed to determine how CIN contributes to tumorigenesis have relied on transgenic mouse models that deliberately increase the rate of chromosomal mis-segregation. Here we develop a strain of transgenic mice that is designed to strategically decrease the rate of chromosome mis-segregation and suppress CIN. These animals modestly overexpress the kinesin-13 microtubule depolymerase Kif2b, a strategy proven successful in restoring faithful chromosome segregation to human cancer cells in culture. Using the LA2 K-Ras G12D-induced model for lung cancer, we show that Kif2b expression reduces the number of chromosome segregation defects but does not change the incidence of lung tumor lesions. However, pulmonary tumors were significantly larger in animals expressing Kif2b and those tumors exhibited elevated rates of Ki-67 positive cells relative to controls. Thus, in lung cancers driven by mutations in K-Ras, CIN has little impact on tumor initiation but suppresses tumor growth. These data support a model in which CIN imposes a burden on tumor cells, and that enhancement of mitotic fidelity results in accelerated tumor growth.
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PMID:Chromosomal instability suppresses the growth of K-Ras-induced lung adenomas. 3117 49