Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is growing interest in studying the molecular mechanisms of crosstalk between cancer metabolism and the cell cycle. 6-phosphate fructose-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a well-known glycolytic activator that plays an important role in tumorigenesis. We investigated whether PFKFB3 was directly involved in oncogenic signaling networks. Mass Spectrometry showed that PFKFB3 interacts with cyclin-dependent kinase (CDK) 4, which controls the transition from G1 phase to S phase of the cell cycle. Further analysis indicated that lysine 147 was a key site for the binding of PFKBFB3 to CDK4. PFKFB3 binding resulted in the accumulation of CDK4 protein by inhibiting ubiquitin proteasome degradation mediated by the heat shock protein 90-Cdc37-CDK4 complex. The proteasome-dependent degradation of CDK4 was accelerated by disrupting the interaction of PFKFB3 with CDK4 by mutating lysine (147) to alanine. Blocking PFKFB3-CDK4 interaction improved the therapeutic effect of FDA-approved CDK4 inhibitor palbociclib on breast cancer. These findings suggest that PFKFB3 is a hub for coordinating cell cycle and glucose metabolism. Combined targeting of PFKFB3 and CDK4 may be new strategy for breast cancer treatment.
 ...
PMID:Non-canonical roles of PFKFB3 in regulation of cell cycle through binding to CDK4. 2933 21