Cyclin-dependent kinase 7, or cell division protein kinase 7, is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''CDK7''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
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 fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
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 th ...
, 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
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 th ...
, and are known to be important regulators of
cell cycle progression
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subse ...
.
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 family, whose members are characterized by a dramatic periodicity in protein abundance thro ...
and
MAT1
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 and ...
, which functions as a Cdk-activating kinase (CAK). It is an essential component of the transcription factor
TFIIH
Transcription factor II Human (transcription factor II H; TFIIH) is an important protein complex, having roles in transcription of various protein-coding genes and DNA nucleotide excision repair (NER) pathways. TFIIH first came to light in 1989 ...
, 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 eg 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
Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the ''CDK7'' gene.
The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are h ...
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 convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...
(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
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
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 family, whose members are characterized by a dramatic periodicity in protein abundance thro ...
,
* GTF2H1
General transcription factor IIH subunit 1 is a protein that in humans is encoded by the ''GTF2H1'' gene.
Interactions
GTF2H1 has been shown to interact with:
* Cyclin-dependent kinase 7,
* E2F1,
* ERCC2,
* Estrogen receptor alpha,
* TCEA ...
,
* 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 and ...
,
* P53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
,[
* ]SUPT5H
Transcription elongation factor SPT5 is a protein that in humans is encoded by the ''SUPT5H'' gene.
Interactions
SUPT5H has been shown to interact with:
* CDK9,
* Cyclin-dependent kinase 7,
* HTATSF1,
* PIN1,
* POLR2A,
* PRMT1 and
* Pr ...
,[ and
* ]XPB
XPB (xeroderma pigmentosum type B) is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.
Structure
The 3D-structure of the archaeal homolog of XPB has been solved by X-ray crystallography by Dr. Jo ...
.
See also
* Cyclin-dependent kinase
Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They a ...
* CDK7 pathway
CDK7 is a cyclin-dependent kinase shown to be not easily classified. CDK7 is both a CDK-activating kinase (CAK) and a component of the general transcription factor TFIIH.
Introduction
An intricate network of cyclin-dependent kinases (CDKs) are or ...
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