CDK20 (cell cycle related kinase)

2009-07-01 Marie Lin , William Cheung Affiliation

Department of Chemistry, Open Laboratory of Chemical Biology, The University of Hong Kong, Pokfulam, Hong Kong, China.

Identity

HGNC

CDK20

LOCATION

9q22.1

LOCUSID

23552

ALIAS

CCRK,CDCH,P42,PNQALRE

FUSION GENES

Show Gene Fusions

DNA/RNA

(A) Chromosomal location of human CCRK gene. (B) Genomic organization of four CCRK transcript variants.

Description

Human CCRK gene spans around 8.3kb of genomic DNA on the chromosome 9q22.2 in telomere-to-centromere orientation. This gene locates within the locus tag RP11-350E12.2. A block of hypermethylated CpGs has been identified in the CCRK promoter and is associated with its high expression in adult human brain cortex (Farcas et al., 2009).

Transcription

Four alternative spliced transcript variants of CCRK gene are known. The generic variant 3 (GenBank#: NM_001039803) consists of 8 exons, with the start codon on exon 1 and stop codon on exon 8. Both transcript variant 1 (GenBank#: NM_178432) and variant 2 (GenBank#: NM_012119) have had their exon 5 deleted. Variant 1 also differs from the other variants by an additional 39nt on exon 2. The cardiac splice variant (GenBank#: AY904367) lacks both the exons 5 and 6, and has truncated 5- and 3-untranslated regions.

Pseudogene

No pseudogenes for CCRK are known.

Proteins

Note

There has been controversy over whether CCRK functions as a second cyclin-dependent kinase (CDK)-activating kinase (CAK) (i.e., in addition to CDK7). Inconsistent with other studies, Wohlbold and colleagues (2006) reported that monomeric CCRK has no intrinsic CAK activity.

Description

The open reading frame encodes a 346-amino acid protein, with molecular weight of 42kDa. CCRK protein has a protein kinase domain extending from residues 4-288, in which typical ATP-binding region and serine/threonine kinase active site can be identified. Its interacting proteins include CDK2, cyclin H and casein kinase 2.

Expression

In human tissues, the 2.2kb CCRK transcript is expressed predominantly in the brain and kidney, and to lesser extent in the liver, heart and placenta. The cardiac CCRK isoform is detectable only in heart, liver and kidney. CCRK is also widely expressed in cell lines originating from glioblastoma (U87, U118, U138, U373 and SW1088), cervical adenocarcinoma (HeLa), colorectal carcinoma (HCT116), osteogenic sarcoma (U2OS), breast adenocarcinoma (MCF-7), ovarian carcinoma (UACC-1598, UACC-326, OVCAR-3, HO-8910 and TOV-21G), lung fibroblast (WI-38), myoblast (C2C12), and lymphocyte (GM08336).

Localisation

Mainly in nucleus and perinuclear region. Relative low expression in cytoplasm.

Function

CCRK is an important regulator of G1- to S-phase transition in cell cycle and is indispensable for cell growth. It possesses CDK-activating kinase activity that is essential for the phosphorylation of CDK2 at Thr160 (Liu et al., 2004) and male germ cell-associated kinase-related kinase (MRK) at Thr157 in mammalian cells (Fu et al., 2006). CCRK also acts as a negative regulator of apoptosis and may confer cells with drug resistance (MacKeigan et al., 2005). Moreover, CCRK splice variant expressing in the heart has been shown to promote cardiac cell growth and survival (Qiu et al., 2008).

Homology

CCRK belongs to the CDK family. Among the other 10 CDK members, human CCRK shares the highest sequence identity (43%) with a well known CAK, CDK7. Orthologs of CCRK are found in orangutans, Old World monkeys, bovine, dog, boar, mouse, rat, fishes, frog, budding yeast and fission yeast.

Implicated in

Entity name

Colorectal carcinoma

Note

Knockdown of CCRK inhibits HCT116 cell proliferation (Wohlbold et al., 2006). A small molecule kinase inhibitor (RGB-286147) that targets CCRK has been shown to promote HCT116 cell death in the absence of cell cycle progression (Caligiuri et al., 2005).

Entity name

Glioblastoma multiforme

Note

In 14 of 19 (74%) human high-grade glioblastoma multiforme patient samples, CCRK mRNA expression levels are more than 1.5-fold higher than those of 3 normal brain tissue samples. By contrast, only 2 of 7 (29%) low-grade glioma samples have elevated CCRK expression. Knockdown of CCRK suppresses glioma tumor growth in mouse xenograft model. CCRK knockdown also inhibits glioblastoma cell proliferation via G1/S-phase arrest and reduction of CDK2 phosphorylation in vitro. Overexpression of CCRK induces malignant transformation of non-tumorigenic glioblastoma cells (U138) both in vitro and in vivo (Ng et al., 2007).

Entity name

Ovarian carcinoma

Note

By CCRK immunohistochemical staining of CCRK in ovarian tissue microarray, CCRK is overexpressed in 65/122 (53%) invasive ovarian carcinoma patient samples, as compared with 22 normal ovarian surface epithelium samples. In 12 pairs of primary ovarian carcinoma and adjacent normal tissue specimens, CCRK expression is elevated in 6 (67%) ovarian carcinoma samples. Ectopic expression of CCRK promotes tumor growth in vivo and ovarian carcinoma cell proliferation in vitro via upregulation of cyclin D1 (Wu et al., 2009).

Prognosis

CCRK expression is positively correlated with ascending histological grade and advanced clinicopathologic features. It is also an independent biomarker for shortened survival time of patients with ovarian carcinoma.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
16242653	2005	A proteome-wide CDK/CRK-specific kinase inhibitor promotes tumor cell death in the absence of cell cycle progression.	Caligiuri M et al
19282513	2009	Differences in DNA methylation patterns and expression of the CCRK gene in human and nonhuman primate cortices.	Farcas R et al
16954377	2006	Identification of yin-yang regulators and a phosphorylation consensus for male germ cell-associated kinase (MAK)-related kinase.	Fu Z et al
14597612	2004	p42, a novel cyclin-dependent kinase-activating kinase in mammalian cells.	Liu Y et al
15864305	2005	Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.	MacKeigan JP et al
17565152	2007	Cell cycle-related kinase: a novel candidate oncogene in human glioblastoma.	Ng SS et al
18508765	2008	Characterization of a novel cardiac isoform of the cell cycle-related kinase that is regulated during heart failure.	Qiu H et al
16552187	2006	The cyclin-dependent kinase (CDK) family member PNQALRE/CCRK supports cell proliferation but has no intrinsic CDK-activating kinase (CAK) activity.	Wohlbold L et al
19672860	2009	Cell cycle-related kinase supports ovarian carcinoma cell proliferation via regulation of cyclin D1 and is a predictor of outcome in patients with ovarian carcinoma.	Wu GQ et al

Other Information

Locus ID:

NCBI: 23552
MIM: 610076
HGNC: 21420
Ensembl: ENSG00000156345

Variants:

dbSNP: 23552
ClinVar: 23552
TCGA: ENSG00000156345
COSMIC: CDK20

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000156345	ENST00000325303	Q8IZL9
ENSG00000156345	ENST00000336654	Q8IZL9
ENSG00000156345	ENST00000375871	Q8IZL9
ENSG00000156345	ENST00000375883	Q8IZL9
ENSG00000156345	ENST00000605159	Q8IZL9
ENSG00000156345	ENST00000605159	A0A0S2Z5B6

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37469151	2023	The Role of CDK20 Protein in Carcinogenesis.	1
37469151	2023	The Role of CDK20 Protein in Carcinogenesis.	1
35609210	2022	BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1.	9
35609210	2022	BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to intraflagellar transport turnaround involving ICK/CILK1.	9
28939663	2018	Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy.	97
28939663	2018	Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy.	97
25500144	2015	A CCRK-EZH2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients.	41
25500144	2015	A CCRK-EZH2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients.	41
23743448	2013	CCRK depletion inhibits glioblastoma cell proliferation in a cilium-dependent manner.	57
23743448	2013	CCRK depletion inhibits glioblastoma cell proliferation in a cilium-dependent manner.	57
22875024	2012	Functional genomics identifies drivers of medulloblastoma dissemination.	24
22875024	2012	Functional genomics identifies drivers of medulloblastoma dissemination.	24
21747169	2011	Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis.	61
21747169	2011	Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis.	61
20466538	2010	Functional characterisation of cell cycle-related kinase (CCRK) in colorectal cancer carcinogenesis.	13

Citation

Marie Lin ; William Cheung

CDK20 (cell cycle related kinase)

Atlas Genet Cytogenet Oncol Haematol. 2009-07-01

Online version: http://atlasgeneticsoncology.org/gene/43196/haematological-explorer/gene-explorer/case-report-explorer/