CKS2 (CDC28 protein kinase regulatory subunit 2)

2010-02-01 Yongyou Zhang Affiliation

Case Western Reserve University, WRB-3101, 2103 Cornell Rd, Cleveland, OH 44106, USA

Identity

HGNC

CKS2

LOCATION

9q22.2

LOCUSID

1164

ALIAS

CKSHS2

FUSION GENES

Show Gene Fusions

DNA/RNA

Genomic organization of the CKS2 gene.

Description

Three exons, spans approximately 5.5 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon ATG is located in exon 1, and the stop codon in exon 3.

Transcription

mRNA is 627 bp.

Pseudogene

1 processed, non-expressed, pseudogene in human genome.

Proteins

Note

The Cks2 protein can form a special homohexamer structure. Six kinase subunits can bind the assembled hexamer, and therefore this Cks2 hexamer may participate in cell cycle control by acting as the hub for Cdk multimerization in vivo.

Description

The open reading frame encodes a 79 amino acid protein, with an estimated molecular weight of approximately 9860 Da.

Expression

Basic level expression in all mammalian cells and aberrant expression in cancer cells.

Localisation

Cytoplasm and nucleus.

Function

CKS2 protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function of cell cycle control. Especially, CKS2 is required for the first metaphase/anaphase transition of mammalian meiosis. The mice ablated of Cks2 are viable but sterile in both sexes. Sterility is due to failure of both male and female germ cells to progress from the first meiotic metaphase to anaphase. In cancer cells, CKS2 may protect the cells from apoptosis.

Homology

The CKS2 protein is evolutionary conserved. Mammalian cells express two well-conserved CKS members, like the human CKS2 and CKS1B proteins. CKS2 and CKS1B may have redundant function in some context and have different functions in other context. The CKS2 protein is highly conserved cross species.

Mutations

Note

Mutation of glutamine for glutamate 63 (E63Q), disrupted the essential biological function of the protein and significantly reduced its ability to bind to cyclin-dependent kinases, but preserves protein structure and assembly.

Implicated in

Entity name

Various cancers

Note

Emerging evidence showed that the expression of CKS2 is elevated in multiple cancers, including prostate cancer, breast cancer, gastric cancer, colorectal cancer, uterine cervical cancer, bladder cancer, nasopharyngeal carcinoma, melanoma, lymphoma, lung cancer, esophageal squamous cell carcinoma et al. The expression of CKS2 is correlated with poor survival rate of the patients of some cancers.

Prognosis

Overexpression of CKS2 has been reported to be associated with high aggressiveness and a poor prognosis in multiple cancers, including breast cancer, prostate cancer, colon cancer, hepatocellular carcinoma and meningiomas et al.

Entity name

Hepatocellular carcinoma (HCC)

Note

Expressions of CKS2 were significantly higher in HCC compared with the adjacent noncancerous tissues (including chronic hepatitis and cirrhosis) and normal liver tissues. Overexpression of CKS2 in HCC were closely associated with poor differentiation features (Shen et al., 2010).

Entity name

Gastric cancer

Note

CKS2 was showed to be significantly unregulated in gastric cancers. The high level of CKS2 was highly correlated with tumor differentiation and pathological grade of the tumor size, lymph node, and metastasis stage (Kang et al., 2009).

Entity name

Prostate cancer

Note

CKS2 were significantly unregulated in prostate tumors of human and animal models, as well as prostatic cancer cell lines. Forced expression of CKS2 in benign prostate tumor epithelial cells promoted cell population growth. Inhibition of CKS2 expression can induce programmed cell death and inhibit the tumorigenesis. (Lan et al., 2008). Over expression of CKS2 may linked with androgen-independent prostate cancer progression (Stanbrough et al., 2006).

Entity name

Colon cancer

Note

CKS2 was reported significantly overexpressed in microdissected invasive colon tumor cells compared with adjacent normal epithelial cells (Wiese et al., 2007). CKS2 was also showed to be higher in liver metastasis compared with primary colon cancer (Lin et al., 2007).

Oncogenesis

Amplification and overexpression of CKS2 were associated with liver metastasis and poor prognosis in colon cancer. CKS2 is required for germ cell to go past the first meiotic metaphase and enter anaphase. In cancer cell, overexpression of CKS2 can accelerate the cell cycles and promote the cell proliferation. Recently research showed that CKS2 may also be involved in apoptosis and metabolism since it can protect mitochondrial genome integrity via interaction with mitochondrial single-stranded DNA-binding protein. Study also showed CKS2 as a transcriptional target downregulated by the tumor suppressor p53. CKS2 expression was found to be repressed by p53 both at the mRNA and the protein levels, which may provide a mechanism that explain why CKS2 is upregulated in many types of cancer. All of these suggest that CKS2 alterations may have a significant biological role in the tumorigenesis in different tissue. The novel therapeutic strategy for cancer though may be developed via inhibiting the CKS2 activity. Therefore, disruption of CKS2-Cyclin Complex assembly or down-regulation of CKS2 expression may be used for cancer therapy.

Entity name

Esophageal squamous cell carcinoma

Note

Gene expression profiling of lymph node metastasis by oligomicroarray analysis and Real-time RT-PCR confirmed that CKS2 is unregulated in laser microdissection of esophageal squamous cell carcinoma compared with adjacent normal tissue (Uchikado et al., 2006).

Entity name

Uterine cervical cancer

Note

CKS2 was showed significantly higher in node positive tumor compared with negative one. The CKS2 expression is correlated with metastatic phenotypes and progression free survival. (Lyng et al., 2006).

Entity name

Bladder cancer

Note

Large-scale gene expression profiling and Real-Time RT-PCR confirmed that a the CKS2 expression is elevated in invasive bladder cancer compared with superficial cancer (Kawakami et al., 2006).

Entity name

Glioblastoma

Note

CKS2 was significantly up-regulated in primary glioblastomas compared with the non-neoplastic brain tissues (Scrideli et al., 2008).

Entity name

Meningioma

Note

This microarray-based expression profiling study showed CKS2 is unregulated in atypical and anaplastic meningiomas compared with benign meningiomas (Fevre-Montange et al., 2009).

Bibliography

Pubmed ID	Last Year	Title	Authors
16116475	2006	Identification of RASSF1A modulated genes in nasopharyngeal carcinoma.	Chow LS et al
8697818	1996	Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22.	Demetrick DJ et al
12851469	2003	Germline exclusion of Cks1 in the mouse reveals a metaphase I role for Cks proteins in male and female meiosis.	Donovan PJ et al
9632748	1998	Cyclin-stimulated binding of Cks proteins to cyclin-dependent kinases.	Egan EA et al
19885562	2009	Microarray gene expression profiling in meningiomas: differential expression according to grade or histopathological subtype.	Fèvre-Montange M et al
18005268	2008	Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis.	Haaber J et al
19034516	2009	Upregulation of the cycline kinase subunit CKS2 increases cell proliferation rate in gastric cancer.	Kang MA et al
16865252	2006	Identification of differentially expressed genes in human bladder cancer through genome-wide gene expression profiling.	Kawakami K et al
18498131	2008	Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death.	Lan Y et al
14719106	2004	Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray.	Li M et al
17428314	2007	Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer.	Lin CY et al
17487416	2007	Genome wide expression profiling identifies genes associated with colorectal liver metastasis.	Lin HM et al
12695690	2003	PC-SPES inhibits cell proliferation by modulating p21, cyclins D, E and B and multiple cell cycle-related genes in prostate cancer cells.	Lu X et al
17054779	2006	Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer.	Lyng H et al
18625720	2008	Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells.	Martinsson-Ahlzén HS et al
19837160	2010	Clinical, pathological, proliferative and molecular responses associated with neoadjuvant aromatase inhibitor treatment in breast cancer.	Miller WR et al
8211159	1993	Human CksHs2 atomic structure: a role for its hexameric assembly in cell cycle control.	Parge HE et al
8939596	1996	Cell cycle: reaching for a role for the Cks proteins.	Pines J et al
19786724	2010	CKS proteins protect mitochondrial genome integrity by interacting with mitochondrial single-stranded DNA-binding protein.	Radulovic M et al
17336302	2007	Gene expression of cyclin-dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73.	Rother K et al
18398573	2008	Gene expression profile analysis of primary glioblastomas and non-neoplastic brain tissue: identification of potential target genes by oligonucleotide microarray and real-time quantitative PCR.	Scrideli CA et al
12473461	2003	Weak cooperativity in the core causes a switch in folding mechanism between two proteins of the cks family.	Seeliger MA et al
19845855	2010	Clinical significance and expression of cyclin kinase subunits 1 and 2 in hepatocellular carcinoma.	Shen DY et al
12714746	2003	Requirement of Cks2 for the first metaphase/anaphase transition of mammalian meiosis.	Spruck CH et al
16510604	2006	Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.	Stanbrough M et al
17088971	2006	Gene expression profiling of lymph node metastasis by oligomicroarray analysis using laser microdissection in esophageal squamous cell carcinoma.	Uchikado Y et al
10360827	1999	ckshs expression is linked to cell proliferation in normal and malignant human lymphoid cells.	Urbanowicz-Kachnowicz I et al
19175833	2009	Cross-species hybridization of woodchuck hepatitis viral infection-induced woodchuck hepatocellular carcinoma using human, rat and mouse oligonucleotide microarrays.	Wang F et al
8800213	1996	A mutation in the human cyclin-dependent kinase interacting protein, CksHs2, interferes with cyclin-dependent kinase binding and biological function, but preserves protein structure and assembly.	Watson MH et al
17936523	2007	Identification of gene signatures for invasive colorectal tumor cells.	Wiese AH et al
16353136	2006	Genome-wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray.	Wong YF et al
15900300	2005	Analysis of differential gene expression in human melanocytic tumour lesions by custom made oligonucleotide arrays.	de Wit NJ et al

Other Information

Locus ID:

NCBI: 1164
MIM: 116901
HGNC: 2000
Ensembl: ENSG00000123975

Variants:

dbSNP: 1164
ClinVar: 1164
TCGA: ENSG00000123975
COSMIC: CKS2

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000123975	ENST00000314355	P33552

Expression (GTEx)

100

150

200

250

300

350

400

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

Pathways

Pathway	Source	External ID
Small cell lung cancer	KEGG	ko05222
Pathways in cancer	KEGG	hsa05200
Small cell lung cancer	KEGG	hsa05222

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
18625720	2008	Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells.	47
18498131	2008	Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death.	32
21697511	2012	Cyclin-dependent kinase subunit (Cks) 1 or Cks2 overexpression overrides the DNA damage response barrier triggered by activated oncoproteins.	29
21672358	2011	Cyclin-dependent kinase-associated protein Cks2 is associated with bladder cancer progression.	21
19845855	2010	Clinical significance and expression of cyclin kinase subunits 1 and 2 in hepatocellular carcinoma.	19
19034516	2009	Upregulation of the cycline kinase subunit CKS2 increases cell proliferation rate in gastric cancer.	15
23301842	2013	Clinical significance of overexpressed cyclin-dependent kinase subunits 1 and 2 in esophageal carcinoma.	13
17336302	2007	Gene expression of cyclin-dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73.	12
23121546	2013	Oncogenic potential of cyclin kinase subunit-2 in cholangiocarcinoma.	11
21948653	2011	DNA microarray analysis identifies CKS2 and LEPR as potential markers of meningioma recurrence.	9

Citation

Yongyou Zhang

CKS2 (CDC28 protein kinase regulatory subunit 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-02-01

Online version: http://atlasgeneticsoncology.org/gene/40093/cks2-(cdc28-protein-kinase-regulatory-subunit-2)