Abstract:SummarySelective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 C… Show more
“…For example, whereas CDK6 is a relatively weak client of the Hsp90–Cdc37 pathway, CDK4 is a strong client [ 73 – 76 ] and many of its partner proteins regulate protein folding and complex assembly [ 77 ]. These differences in stability are reflected in the affinities of CDK4 and CDK6 for various regulatory proteins [ 78 ]. Taken together, these results suggest that CDK4 is an unstable protein that is prone to unfolding and whose integrity is dependent on protein association, a model further substantiated by structural studies of a CDK4–Cdc37–Hsp90 complex [ 79 ] (see below).…”
Section: Relating Structure and Functionmentioning
confidence: 99%
“…Mutation drives aberrant activation of CDK4/6–cyclin D [ 252 ]. The p16INK4a D84N mutant shows a stark increase in CDK4 activity relative to WTp16INK4a in an Rb phosphorylation assay [ 253 ], and limited ability to bind to CDKs 4 and 6 in cell-free biochemical direct binding analyses [ 78 ]. Figure 11.…”
Section: Aberrant Mutations/processing—structures Relate To Dysregulamentioning
confidence: 99%
“…Cdc37 also supports CDK4 at the C-terminal lobe between the αC-helix and the loop linking to β4. CDK4 is a stronger Cdc37–Hsp90 client than CDK6 [ 76 ], and this is reflected in the ease with which the CDK can be handed off to partner proteins such as the D-type cyclins and members of the INK4 family [ 78 ]. Figure 12.…”
Section: Macromolecular Cdk-containing Complexes and Electron Microscmentioning
Since their characterization as conserved modules that regulate progression through the eukaryotic cell cycle, cyclin-dependent protein kinases (CDKs) in higher eukaryotic cells are now also emerging as significant regulators of transcription, metabolism and cell differentiation. The cyclins, though originally characterized as CDK partners, also have CDK-independent roles that include the regulation of DNA damage repair and transcriptional programmes that direct cell differentiation, apoptosis and metabolic flux. This review compares the structures of the members of the CDK and cyclin families determined by X-ray crystallography, and considers what mechanistic insights they provide to guide functional studies and distinguish CDK- and cyclin-specific activities. Aberrant CDK activity is a hallmark of a number of diseases, and structural studies can provide important insights to identify novel routes to therapy.
“…For example, whereas CDK6 is a relatively weak client of the Hsp90–Cdc37 pathway, CDK4 is a strong client [ 73 – 76 ] and many of its partner proteins regulate protein folding and complex assembly [ 77 ]. These differences in stability are reflected in the affinities of CDK4 and CDK6 for various regulatory proteins [ 78 ]. Taken together, these results suggest that CDK4 is an unstable protein that is prone to unfolding and whose integrity is dependent on protein association, a model further substantiated by structural studies of a CDK4–Cdc37–Hsp90 complex [ 79 ] (see below).…”
Section: Relating Structure and Functionmentioning
confidence: 99%
“…Mutation drives aberrant activation of CDK4/6–cyclin D [ 252 ]. The p16INK4a D84N mutant shows a stark increase in CDK4 activity relative to WTp16INK4a in an Rb phosphorylation assay [ 253 ], and limited ability to bind to CDKs 4 and 6 in cell-free biochemical direct binding analyses [ 78 ]. Figure 11.…”
Section: Aberrant Mutations/processing—structures Relate To Dysregulamentioning
confidence: 99%
“…Cdc37 also supports CDK4 at the C-terminal lobe between the αC-helix and the loop linking to β4. CDK4 is a stronger Cdc37–Hsp90 client than CDK6 [ 76 ], and this is reflected in the ease with which the CDK can be handed off to partner proteins such as the D-type cyclins and members of the INK4 family [ 78 ]. Figure 12.…”
Section: Macromolecular Cdk-containing Complexes and Electron Microscmentioning
Since their characterization as conserved modules that regulate progression through the eukaryotic cell cycle, cyclin-dependent protein kinases (CDKs) in higher eukaryotic cells are now also emerging as significant regulators of transcription, metabolism and cell differentiation. The cyclins, though originally characterized as CDK partners, also have CDK-independent roles that include the regulation of DNA damage repair and transcriptional programmes that direct cell differentiation, apoptosis and metabolic flux. This review compares the structures of the members of the CDK and cyclin families determined by X-ray crystallography, and considers what mechanistic insights they provide to guide functional studies and distinguish CDK- and cyclin-specific activities. Aberrant CDK activity is a hallmark of a number of diseases, and structural studies can provide important insights to identify novel routes to therapy.
“…CDK6 is expressed at high levels in hematopoietic cells (14), and Cdk6 deficiency is characterized by subtle defects in the hematopoietic system, such as defects in thymocyte development (13,15). CDK6 is also a more robust kinase (as compared with CDK4) with distinct affinities for specific modulatory client proteins, and together, these two Cyclin D-dependent CDKs allow for the creation of a network of finely tuned interactions to regulate cell-cycle progression (16). Activation of the Cyclin D-CDK4/6 complex promotes progression from the G 1 phase into S-phase by phosphorylating several cellular targets, of which the Rb protein is key (17).…”
Section: The Biology Of the Cyclin D-cdk4/6-rb Axismentioning
Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anticancer drug development. Three selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are FDA and European Medicines Agency (EMA) approved for hormone receptor-positive/HER2-negative advanced breast cancer. A major emerging appreciation is that these inhibitors not only are cytostatic, but also play critical roles in the interaction between tumor cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell-cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anticancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anticancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immunotherapy.
“…S3 ). Possibly, the CDK4 inhibitor diminishes the proper folding of CDK4 34 and thus reduces Cyclin D1 binding. The interaction of p53 with Cyclin D1 was further confirmed by plasmid-based overexpression of both components (Fig.…”
The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, and inhibitors to both targets are approved or clinically tested for therapy. However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon MDM2 inhibition. Moreover, the p53 response was also attenuated when co-depleting MDM2 and CDK4 with siRNA, compared to MDM2 single knockdown. The complexes of p53 and MDM2, as well as CDK4 and Cyclin D1, physically associated with each other, suggesting direct regulation of p53 by CDK4. Interestingly, CDK4 inhibition did not reduce p53 binding or histone acetylation at promoters, but rather attenuated the subsequent recruitment of RNA Polymerase II. Taken together, our results suggest that caution must be used when considering combined CDK4 and MDM2 inhibition for patient treatment. Moreover, they uncover a hitherto unknown role for CDK4 and Cyclin D1 in sustaining p53 activity.
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