TISIDB

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm. Nucleus. Membrane. Note=Cytoplasmic when non-complexed. Forms a cyclin D-CDK4 complex in the cytoplasm as cells progress through G(1) phase. The complex accumulates on the nuclear membrane and enters the nucleus on transition from G(1) to S phase. Also present in nucleoli and heterochromatin lumps. Colocalizes with RB1 after release into the nucleus.
Domain	PF00069 Protein kinase domain
Function	Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.

> Gene Ontology [ TOP ]
Biological Process	GO:0000082 G1/S transition of mitotic cell cycle GO:0000086 G2/M transition of mitotic cell cycle GO:0001654 eye development GO:0002088 lens development in camera-type eye GO:0006417 regulation of translation GO:0007050 cell cycle arrest GO:0007346 regulation of mitotic cell cycle GO:0007423 sensory organ development GO:0007623 circadian rhythm GO:0008361 regulation of cell size GO:0009636 response to toxic substance GO:0010035 response to inorganic substance GO:0010038 response to metal ion GO:0010288 response to lead ion GO:0010389 regulation of G2/M transition of mitotic cell cycle GO:0010608 posttranscriptional regulation of gene expression GO:0010948 negative regulation of cell cycle process GO:0010971 positive regulation of G2/M transition of mitotic cell cycle GO:0031099 regeneration GO:0031100 animal organ regeneration GO:0032535 regulation of cellular component size GO:0033574 response to testosterone GO:0034248 regulation of cellular amide metabolic process GO:0034250 positive regulation of cellular amide metabolic process GO:0036296 response to increased oxygen levels GO:0042493 response to drug GO:0043010 camera-type eye development GO:0044770 cell cycle phase transition GO:0044772 mitotic cell cycle phase transition GO:0044839 cell cycle G2/M phase transition GO:0044843 cell cycle G1/S phase transition GO:0045727 positive regulation of translation GO:0045786 negative regulation of cell cycle GO:0045787 positive regulation of cell cycle GO:0045793 positive regulation of cell size GO:0045931 positive regulation of mitotic cell cycle GO:0048144 fibroblast proliferation GO:0048145 regulation of fibroblast proliferation GO:0048146 positive regulation of fibroblast proliferation GO:0048511 rhythmic process GO:0055093 response to hyperoxia GO:0070482 response to oxygen levels GO:0071156 regulation of cell cycle arrest GO:0071157 negative regulation of cell cycle arrest GO:0090066 regulation of anatomical structure size GO:0090068 positive regulation of cell cycle process GO:1901654 response to ketone GO:1901987 regulation of cell cycle phase transition GO:1901989 positive regulation of cell cycle phase transition GO:1901990 regulation of mitotic cell cycle phase transition GO:1901992 positive regulation of mitotic cell cycle phase transition GO:1902749 regulation of cell cycle G2/M phase transition GO:1902751 positive regulation of cell cycle G2/M phase transition
Molecular Function	GO:0004674 protein serine/threonine kinase activity GO:0004693 cyclin-dependent protein serine/threonine kinase activity GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity GO:0019207 kinase regulator activity GO:0019887 protein kinase regulator activity GO:0030332 cyclin binding GO:0097472 cyclin-dependent protein kinase activity
Cellular Component	GO:0000307 cyclin-dependent protein kinase holoenzyme complex GO:0000785 chromatin GO:0005635 nuclear envelope GO:0005667 transcription factor complex GO:0005923 bicellular tight junction GO:0031965 nuclear membrane GO:0043296 apical junction complex GO:0061695 transferase complex, transferring phosphorus-containing groups GO:0070160 occluding junction GO:1902554 serine/threonine protein kinase complex GO:1902911 protein kinase complex

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04110 Cell cycle hsa04115 p53 signaling pathway hsa04151 PI3K-Akt signaling pathway hsa04530 Tight junction hsa04660 T cell receptor signaling pathway
Reactome	R-HSA-1640170: Cell Cycle R-HSA-69278: Cell Cycle, Mitotic R-HSA-2559583: Cellular Senescence R-HSA-2262752: Cellular responses to stress R-HSA-3247509: Chromatin modifying enzymes R-HSA-4839726: Chromatin organization R-HSA-69656: Cyclin A R-HSA-69231: Cyclin D associated events in G1 R-HSA-69202: Cyclin E associated events during G1/S transition R-HSA-1266738: Developmental Biology R-HSA-69236: G1 Phase R-HSA-69206: G1/S Transition R-HSA-1500620: Meiosis R-HSA-912446: Meiotic recombination R-HSA-453279: Mitotic G1-G1/S phases R-HSA-2559585: Oncogene Induced Senescence R-HSA-2559580: Oxidative Stress Induced Senescence R-HSA-8849470: PTK6 Regulates Cell Cycle R-HSA-3214858: RMTs methylate histone arginines R-HSA-69242: S Phase R-HSA-187577: SCF(Skp2)-mediated degradation of p27/p21 R-HSA-2559582: Senescence-Associated Secretory Phenotype (SASP) R-HSA-162582: Signal Transduction R-HSA-8848021: Signaling by PTK6 R-HSA-381340: Transcriptional regulation of white adipocyte differentiation R-HSA-75815: Ubiquitin-dependent degradation of Cyclin D R-HSA-69229: Ubiquitin-dependent degradation of Cyclin D1

> KEGG and Reactome Pathway

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KEGG

hsa04110 Cell cycle
hsa04115 p53 signaling pathway
hsa04151 PI3K-Akt signaling pathway
hsa04530 Tight junction
hsa04660 T cell receptor signaling pathway

Reactome

R-HSA-1640170: Cell Cycle
R-HSA-69278: Cell Cycle, Mitotic
R-HSA-2559583: Cellular Senescence
R-HSA-2262752: Cellular responses to stress
R-HSA-3247509: Chromatin modifying enzymes
R-HSA-4839726: Chromatin organization
R-HSA-69656: Cyclin A
R-HSA-69231: Cyclin D associated events in G1
R-HSA-69202: Cyclin E associated events during G1/S transition
R-HSA-1266738: Developmental Biology
R-HSA-69236: G1 Phase
R-HSA-69206: G1/S Transition
R-HSA-1500620: Meiosis
R-HSA-912446: Meiotic recombination
R-HSA-453279: Mitotic G1-G1/S phases
R-HSA-2559585: Oncogene Induced Senescence
R-HSA-2559580: Oxidative Stress Induced Senescence
R-HSA-8849470: PTK6 Regulates Cell Cycle
R-HSA-3214858: RMTs methylate histone arginines
R-HSA-69242: S Phase
R-HSA-187577: SCF(Skp2)-mediated degradation of p27/p21
R-HSA-2559582: Senescence-Associated Secretory Phenotype (SASP)
R-HSA-162582: Signal Transduction
R-HSA-8848021: Signaling by PTK6
R-HSA-381340: Transcriptional regulation of white adipocyte differentiation
R-HSA-75815: Ubiquitin-dependent degradation of Cyclin D
R-HSA-69229: Ubiquitin-dependent degradation of Cyclin D1

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between CDK4 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between CDK4 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26719346	Melanoma	Inhibit immunity (infiltration)	AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ≤ .005) in an NF-κB-dependent manner.
29160310	Prostate Carcinoma	Promote immunity	Here we show that PD-L1 protein abundance is regulated by cyclin D-CDK4 and the cullin 3-SPOP E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (hereafter CDK4/6) in vivo increases PD-L1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of speckle-type POZ protein (SPOP) and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1. Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumour-infiltrating lymphocytes in mouse tumours and in primary human prostate cancer specimens.

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of CDK4 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of CDK4 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.434	0.209
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.011	0.997
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.759	0.746
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.023	0.943
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.044	0.981
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.113	0.964
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.25	0.584
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.577	0.777
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.151	0.946
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	-0.214	0.923
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.01	0.998
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.143	0.0594

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of CDK4 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	0	0	0	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	0	0	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	5.9	-5.9	0.447
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	16.7	-16.7	0.429
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	2.6	0	2.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of CDK4. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of CDK4. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by CDK4. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of CDK4. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of CDK4 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between CDK4 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	CDK4
Name	cyclin-dependent kinase 4
Aliases	PSK-J3; CMM3; cell division protein kinase 4
Chromosomal Location	12q13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting CDK4 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting CDK4.

ID	Name	Drug Type	Targets	#Targets
DB02733	Purvalanol	Small Molecule	CDK2, CDK4, MAPK1, MAPK3, SRPK2	5
DB03496	Alvocidib	Small Molecule	CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, EGFR, PYGB, PYGL, ......	12
DB09073	Palbociclib	Small Molecule	CDK4, CDK6	2
DB11730	Ribociclib	Small Molecule	CDK4, CDK6	2
DB12001	Abemaciclib	Small Molecule	CDK4, CDK6	2

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