Cyclin-dependent kinases

Cyclin–dependent kinase 4 and 6 are key mediators of cell growth and division, regulating the restriction point, and transition through G1 to S phase of the cell cycle.

Cyclin-dependent kinases (CDKs) are the families of protein kinases regulate the cell cycle, transcription, mRNA processing, and the differentiation of nerve cells.

CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the kinase domain.

A CDK binds a regulatory protein called a cyclin. 

Without cyclin, CDK has little kinase activity.

CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases.

CDK1, with cyclin A2 and B1  can drive the cell cycle.

CDK7, is involved indirectly as the CDK-activating kinase.

Cyclin-CDK complexes phosphorylate substrates appropriate for the particular cell cycle phase..

CDK levels remain relatively constant throughout the cell cycle and most regulation is post-translational. 

The four major mechanisms of CDK regulation are cyclin binding, phosphorylation, regulatory inhibitory phosphorylation, and binding of CDK inhibitory subunits (CKIs).

A cyclin-dependent kinase inhibitor (CKI) is a protein that interacts with a cyclin-CDK complex to block kinase activity, usually during G1 or in response to signals from the environment or from damaged DNA.

CDKs are considered a potential target for anti-cancer medication. 

If selectively interrupting the cell cycle regulation in cancer cells by interfering with CDK action, the cell will die. 

Palbociclib and abemaciclib have been approved for the management of hormone receptor (estrogen receptor/progestogen receptor) expressing metastatic breast cancer in combination with endocrine therapy.

Complications of developing a CDK drug include the fact that many CDKs are not involved in the cell cycle, but other processes such as transcription, neural physiology, and glucose homeostasis.

High cyclin D1 expression is a dominant feature of estrogen receptor positive breast cancer and is associated with a worse prognosis, and endocrine resistance.

Cyclin–dependent kinase 4 and 6 are critical regulators of ER positive breast cancer cell proliferation.

Interact with cyclin D proteins to promote cell cycle progression and contribute to tumorigenesis and proliferation in several malignancies.

CDKs 4 and 6 (CDK4/6) interact with cyclin D subunits to phosphorylate the retinoblastoma tumor suppressor gene facilitationg progression through the G1-S phase cell cycle checkpoint.

Cyclin-dependent kinases four and six promote continued cell cycle progression and growth in cancer.

Cyclin-dependent kinases-CDK4/6 target a molecular pathway, the cycling D-CDK 4/6-retinoblastoma tumor suppressor gene axis which is often altered in breast cancer.

Specific CDK 4/6 alterations lead to resistance to endocrine therapy in hormone reset with insecurity positive breast cancer.

The family of proteins known as CDKs control the complex process of cell division, and are often dysfunctional in cancer cells, fueling aberrant division and uncontrolled cell growth.

A large family of enzymes divided into two groups: those that control cell cycle progression and those that control transcriptional events.

CDK’s 1,2,3,4,6 control progression through the various phases of the cell cycle, such as the transitions from G1 to S, S to G2, and G2 to M phase, as well as mitotic progression.

CDK inhibition shuts down the cell cycle and prevents cells from growing.

CDK 4and 6 have a change the standard of care for patients with advanced hormone receptor positive breast cancer.

Transcriptional CDKs control the initiation and the elongation of the mRNA transcripts by phosphorylating the C-terminal domain of the RNA polymerase II, which makes messenger RNA/.

In malignant cells, cells cycle CDKs are frequently dysregulated and control of the transcriptional CDKs may also be altered.

Activated by their association with cyclins.

A cyclin forms a complex with a CDK-the active holoenzyme.

All cells contain endogenous inhibitors CDKs, so these kinases are activated only one they should be, and so is tightly regulated.

Active growing cells such as hair cells, lung lining cells G.I. tract cells, bone marrow cells and skin cells are tightly regulated by inhibitors.

Cancer cells may have their inhibitors missing.

Malignant cells frequently have overactivity of the cell cycle CDKs.

CDKs 4 and 6 contribute to control of progression through G1 phase of the cell cycle, and which pair with D-cyclins to from holoenzymes.

There may be overexpression of D-cyclin genes or amplification of the genes that include CDK4 or CK6 6 leading to their overexpression.

Most commonly, mutation, deletion, or promoter methylation of the genes encoding endogenous CK4/6 inhibitors allows CDKs 4 and 6 to continually drive cell cycle progression giving cancer cells a growth advantage.

Palbociclip ,abemaciclib, and ribociclib significantly prolong progression free survival when it administered in combination with endocrine therapy as first-line treatment in women with a hormone receptor positive metastatic breast cancer.

The primary adverse effects with palcociclip and ribociclib is neutropenia without an increase in the risk of febrile neutropenia.

The primary adverse effect with abemaclib is diarrhea.

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