Disease	Score

Substances	Interaction	Organism	Category

Substances	Interaction	Organism	Category

Cyclin-dependent kinase 6 (CDK6)

CDK6 is a member of the cyclin-dependent kinase family of genes, whose members act to ensure normal cell replication and division [R].

CDK6 has been shown to inactivate a protein called Retinoblastoma (Rb) by adding a phosphate chemical group, in a process called phosphorylation, to this Rb protein [R]. This has the effect of preventing the protein Rb from carrying out its normal tumor-suppression property of preventing DNA replication [R, R2, R3].

The action of CDK6, along with other members of the cyclin-dependent kinase family, in halting the tumor-suppression function of protein Rb, allows a cell to replicate and divide (Mitosis) in order to form a new daughter cell [R, R2].

Throughout  Mitosis, another protein named Protein Phosphatase 1 (PP1) returns Rb to its original state by removing the phosphate groups previously added by CDK6 [R, R2]. This entire cell-cycle process is repeated each time a cell undergoes Mitosis [R].

There are implications for a role of CDK6 in preventing cancer, as well as for a role in  causing of cancer.

CDK6 may have a secondary function in addition to acting as a switch on the Rb protein, by acting as an anti-tumor gene. It does this by recognizing DNA damage and acting to prevent that damaged cell from reproducing itself [R, R2, R3, R4].  

A correlation has been shown between a malfunction of this tumor-suppressor property and blood cell cancers, as well as with cancers of the lymphatic system (white blood cells, bone marrow, the spleen, thymus gland, and various tissues throughout the body) [R, R2].

A study of patients with estrogen receptor-positive breast cancer, the most common sub-type of breast cancer, who are resistant to current hormone therapy benefit if the activity of CDK6 is inhibited when receiving their prescribed hormone therapy.

This hints that this population of estrogen receptor-positive breast cancer patients may benefit from having CDK4 and CDK6 inhibitors added to their current treatment regimens [R, R2, R3]. A new generation of drugs is being developed to inhibit CDK4 and CDK6 for those patients with estrogen receptor-positive breast cancer and a naturally high activity of CDK6 [R, R2, R3].

An examination of throat tissues, suggests that increased levels of CDK6 are associated with the development and progression of the most common type of throat cancer nasopharyngeal carcinoma (NPC) [R].

     From NCBI Gene: Primary autosomal recessive microcephaly 12From UniProt: Microcephaly 12, primary, autosomal recessive (MCPH12): A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. [MIM:616080]

     From NCBI Gene: The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb. Expression of this gene is up-regulated in some types of cancer. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2009] From UniProt: Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans. May play a role in the centrosome organization during the cell cycle phases (PubMed:23918663).

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

Condition	Change (log2fold)	Comparison	Species	Experimental variables	Experiment name

The following transcription factors affect gene expression:

• ER-alpha
• C/EBPalpha
• GATA-1
• E2F-1
• AML1a
• GATA-3
• Sox5

Tissue specificity:

Expressed ubiquitously. Accumulates in squamous cell carcinomas, proliferating hematopoietic progenitor cells, beta-cells of pancreatic islets of Langerhans, and neuroblastomas. Reduced levels in differentiating cells.

Induction:

Down-regulated in response to enterovirus 71 (EV71) infection. Induced by NANOG during S-phase entry.

Enzyme Regulation:

Inhibited by INK4 proteins (CDKN2C/p18-INK4c), aminopurvalanol, PD0332991, 4-(Pyrazol-4-yl)-pyrimidines and fisetin, a flavonol inhibitor. Activated by Thr-177 phosphorylation and Tyr-24 dephosphorylation (By similarity). Stimulated by cyclin from herpesvirus saimiri (V-cyclin/ECLF2). Rapidly down-regulated prior to cell differentiation (e.g. erythroid and osteoblast).

Molecular Function:

• Atp Binding
• Cyclin Binding
• Cyclin-Dependent Protein Serine/Threonine Kinase Activity
• Fbxo Family Protein Binding

Biological Processes:

• Astrocyte Development
• Cell Cycle Arrest
• Cell Dedifferentiation
• Cell Division
• Cellular Response To Phorbol 13-Acetate 12-Myristate
• Dentate Gyrus Development
• G1/S Transition Of Mitotic Cell Cycle
• Generation Of Neurons
• Gliogenesis
• Lateral Ventricle Development
• Negative Regulation Of Cell Cycle
• Negative Regulation Of Cell Differentiation
• Negative Regulation Of Cell Proliferation
• Negative Regulation Of Cellular Senescence
• Negative Regulation Of Epithelial Cell Proliferation
• Negative Regulation Of Monocyte Differentiation
• Negative Regulation Of Myeloid Cell Differentiation
• Negative Regulation Of Osteoblast Differentiation
• Positive Regulation Of Cell-Matrix Adhesion
• Positive Regulation Of Fibroblast Proliferation
• Protein Phosphorylation
• Regulation Of Cell Motility
• Regulation Of Erythrocyte Differentiation
• Regulation Of Gene Expression
• Response To Virus
• Type B Pancreatic Cell Development
• Hematopoietic Stem Cell Differentiation
• Notch Signaling Pathway
• Positive Regulation Of Gene Expression
• T Cell Differentiation In Thymus

Drug Bank:

• Palbociclib

*synonyms