Cyclin-dependent kinase 7, or cell division protein kinase 7, is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''CDK7''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
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
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
cdc28
Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in t ...
, and
Schizosaccharomyces pombe
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...
cdc2, and are known to be important regulators of
cell cycle progression.
This protein forms a trimeric complex with
cyclin H
Cyclin-H is a protein that in humans is encoded by the ''CCNH'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin
Cyclins are proteins that control the progression of a cell through the cell cycle by ac ...
and
MAT1, which functions as a Cdk-activating kinase (CAK). It is an essential component of the transcription factor
TFIIH, that is involved in transcription initiation and DNA repair. This protein is thought to serve as a direct link between the regulation of transcription and the cell cycle.
Clinical significance e.g. cancer
Given that CDK7 is involved in two important regulation roles, it's expected that CDK7 regulation may play a role in cancerous cells. Cells from breast cancer tumors were found to have elevated levels of CDK7 and Cyclin H when compared to normal breast cells. It was also found that the higher levels were generally found in ER-positive breast cancer. Together, these findings indicate that CDK7 therapy might make sense for some breast cancer patients.
Further confirming these findings, recent research indicates that inhibition of CDK7 may be an effective therapy for HER2-positive breast cancers, even overcoming therapeutic resistance. THZ1 was tested on HER2-positive breast cancer cells and exhibited high potency for the cells regardless of their sensitivity to HER2 inhibitors. This finding was demonstrated in vivo, where inhibition of HER2 and CDK7 resulted in tumor regression in therapeutically resistant HER2+ xenograft models.
Inhibitors
The growth suppressor p53 has been shown to interact with cyclin H both in vitro and in vivo. Addition of wild type p53 was found to heavily downregulated CAK activity, resulting in decreased phosphorylation of both CDK2 and CTD by CDK7. Mutant p53 was unable to downregulate CDK7 activity and mutant p21 had no effect on downregulation, indicating that p53 is responsible for negative regulation of CDK7.
In 2017 CT7001, an oral CDK7 inhibitor, started a phase 1 clinical trial.
THZ1 is an inhibitor for CDK7 that selectively forms a covalent bond with the CDK7-cycH-MAT1 complex. This selectivity stems from forming a bond at C312, which is unique to CDK7 within the CDK family. CDK12 and CDK13 could also be inhibited using THZ1 (but at higher concentrations) because they have similar structures in the region surrounding C312.
It was found that treatment of 250 nM THZ1 was sufficient to inhibit global transcription and that cancer cell lines were sensitive to much lower concentrations, opening up further research into the efficacy of using THZ1 as a component of cancer therapy, as described above.
In
renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cance ...
(RCC), the expression of CDK7 was significantly higher in the advanced stage tumors. Besides, the overall survival was significantly shorter in patients with higher CDK7 expression in the tumors. These results suggest that CDK7 may be a potential target for overcoming RCC.
Based on molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms. Analysis of MD simulations and MM-PBSA studies, revealed the binding energy profiles of all the selected complexes. Selected ligands performed better than the experimental drug candidate (Roscovitine). Ligands-3 and 14 show specificity for CDK7. These ligands are expected to possess lower risk of side effects due to their natural origin.
In urothelial carcinoma (UC), CDK7 expression is increased in bladder cancer tissues, especially in patients with chemoresistance. CDK7 inhibition-related cancer stemness suppression is a potential therapeutic strategy for both chemonaïve and chemoresistant UC.
Interactions
Cyclin-dependent kinase 7 has been shown to
interact with:
*
Androgen receptor
The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...
,
*
Cyclin H
Cyclin-H is a protein that in humans is encoded by the ''CCNH'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin
Cyclins are proteins that control the progression of a cell through the cell cycle by ac ...
,
* GTF2H1,
* MNAT1
CDK-activating kinase assembly factor MAT1 is an enzyme that in humans is encoded by the ''MNAT1'' gene.
Function
Cyclin-dependent kinases (CDKs), which play an essential role in cell cycle control of eukaryotic cells, are phosphorylated an ...
,
* P53
p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
,[
* SUPT5H,][ and
* XPB.]
See also
* Cyclin-dependent kinase
Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzym ...
* CDK7 pathway
References
Further reading
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External links
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{{DEFAULTSORT:Cyclin-dependent kinase 07
Cell cycle
Proteins
EC 2.7.11