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Cyclin-dependent kinase 4 (CDK4), also known as cell division protein kinase 4, is an enzyme that is encoded by the CDK4 gene in humans. CDK4 is a member of the cyclin-dependent kinase family, a group of serine/threonine kinases which regulate the cell cycle. CDK4 regulates the G1/S transition by contributing to the phosphorylation of retinoblastoma (RB) protein, which leads to the release of protein factors like E2F1 that promote S-phase progression. It is regulated by like cyclin D proteins, regulatory kinases, and cyclin kinase inhibitors (CKIs). Dysregulation of the CDK4 pathway is common in many cancers, and CDK4 is a new Drug target in cancer treatment.
Notably, CDK6 is very related to CDK4 in both structure and function. They share 71% of their amino acids and both regulate the G1/S transition by phosphorylating Rb. CDK4 and 6 differ in their cellular localization and other off-pathway roles, however are commonly referred together as CDK4/6.
The CDK4 protein is similar to the fungi gene products of S. cerevisiae cdc28 and S. pombe cdc2.
There are two models of CDK4 cell cycle regulation. The older model proposes that the kinase is responsible for the phosphorylation of retinoblastoma gene product (Rb). The Ser/Thr-kinase component of cyclin D-CDK4 (DC) forms complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1 phase. In this model, CDK4 inhibits Rb, which inhibits E2F, which promotes progression into S phase.
The newer model, as proposed in a 2014 paper by Narasimha et al., The CDK4-cyclin D complex phosphorylates the retinoblastoma tumor suppressor protein (Rb) and its related proteins p107 and p130, which go on to inhibit cell cycle progression. As a kinase, the CDK4 serine/threonine active site converts ATP to ADP and transfers the removed phosphate group to Rb. Rb is mono-phosphorylated in early G1 by the CDK4-cyclin D complex. When mono-phosphorylated, Rb exists as one of the 14 isoforms, which bind to protein factors like E1a, and proteins in the E2F family.
The new model of CDK4 regulation posits that at the G1/S checkpoint, if a cell seems healthy, CDK2 (a different cyclin dependent kinase) inactivates Rb, and these protein factors are released back into the cell. E2F proteins then activate the transcription of genes that cause S-phase progression. However, if at the G1/S checkpoint a cell detects DNA damage, it will response by activating the CDK4-cyclin D complex to mono-phosphorylate, and activate Rb. This prevents Rb from dissociating from E2F protins, which prevents them from activating the transcription of the S-phase progression genes.
While CDK4 primarily regulates the cell cycle through phosphorylation of Rb, there is evidence of a secondary, more direct role independent of Rb. CDK4 may be able to directly phosphorylate transcription factors and co-regulators like Smad3, MYC, FOXM1, and MEP50 to regulate the cell cycle, survival and senescence.
Interestingly, CDK4-null mutant mice are viable, and in-vitro experiments show that cell proliferation is not significantly affected, likely due to compensatory roles played by other CDKs. However, CDK plays a significant role in cancer development.
CDK4 activity is positively regulated by cyclin D, which creates a conformational change in CDK4 that opens the active site for kinase activity. Cyclins are proteins that change concentration periodically during the cell cycle. They are extremely specific and diverse, which serves to regulate the cell cycle with precision. Cyclin D levels oscillate during the G1 phase, first increasing and accumulating, then rapidly decreasing during the transition to the S phase. Cyclin D levels are stimulated by growth factors, without which cyclin D levels would stay low regardless of cell cycle stage. After its role in G1 is complete, cyclin D is translocated from the nucleus to the cytoplasm in S phase, modulating the nuclear cyclin D levels, and therefore modulating the activity of CDK4 to promote the S phase transition.
Mutations in the CDK4 gene as well as in its related proteins including D-type cyclins, p16(INK4a), CDKN2A and Rb were all found to be associated with tumorigenesis of a variety of cancers, including sarcomas, gliomas, lymphomas and tumors of the mammary gland. One specific point mutation of CDK4 (R24C) was first identified in melanoma patients. This mutation was introduced also in animal models and its role as a cancer driver oncogene was studied thoroughly. Nowadays, deregulated CDK4 is considered to be a potential therapeutic target in some cancer types and various CDK4 inhibitors are being tested for cancer treatment in clinical trials. Multiple polyadenylation sites of this gene have been reported.
Cyclin D and CDK4/6 activities are observed to be up-regulated in certain cancers, sparking interest in the development of small-molecule inhibitors of CDK4/6. Ribociclib are US FDA approved CDK4 and CDK6 inhibitors for the treatment of estrogen receptor positive/ HER2 negative advanced breast cancer.
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