PLK1 (polo-like kinase 1 (Drosophila))

2005-04-01   Ayse Elif Erson , Elizabeth M. Petty 

Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA (EMP)

Identity

HGNC
LOCATION
16p12.2
LOCUSID
ALIAS
PLK,STPK13
FUSION GENES

DNA/RNA

Atlas Image
The alignment of PLK1 mRNA (NM_005030) to its genomic sequence NC_000016).

Description

PLK1 mRNA spans approximately 11.5 kb and has 10 exons. The sizes of the exons 1 to 10 are 461, 169, 145, 94, 220, 156, 78, 155, 183 and 508 bps.

Transcription

PLK1 mRNA (NM_005030) is 2204 bp. PLK1 expression is believed to reach its peak value in mitosis in the cell cycle. It is highly expressed in actively proliferating tissues such as those in the placenta, spleen, ovary, and testis. High expression of PLK1 is also detected in various neoplastic tissues. Northern blot analysis reveals low or undetectable levels of PLK1 transcript in most other adult tissues (e.g.: brain, thymus, liver, lung, pancreas, heart, kidney, stomach, intestine and skin).

Pseudogene

Mouse Plk gene maps to Chromosome 7 and the processed pseudogene to mouse Chromosome 5. No human pseudogene for PLK1 has been reported.

Proteins

Description

Protein consists of 603 amino acids and is 66kDa. In addition to the N-terminus kinase domain, there are two conserved polo-box regions of 30 amino acids at the C-terminus. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for both auto-inhibition and sub-cellular localization.

Expression

PLK1 protein becomes a target of the anaphase-promoting complex/cyclosome and is degraded by the ubiquitin-proteasome pathway as cells exit mitosis.

Localisation

During interphase, PLK1 localizes to centrosomes. In early mitosis, it associates with mitotic spindle poles. A recombinant GFP-PLK1 protein localizes to centromere/kinetochore region, suggesting a possible role for chromosome separation.

Function

PLK1 is believed to be involved in the regulation of key steps during cell division, DNA damage repair pathways, apoptosis, and the progression of the cell cycle.
PLK1 has roles in the activation of cdc2 through cdc25 and direct phosphorylation of cyclin B1, through which MPF (mitosis promoting factor) is activated so that mitosis can start.
Microinjection of PLK1 antibodies causes failure of g-tubulin recruitment to the centrosomes. This failure results in immature centrosomes and monopolar spindle formation. Similar microinjection experiments in cell lines (transformed HeLa and non-immortalized Hs68 fibroblasts) result in a marked inhibition of cell cycle progression.
PLK1 also has a possible role during cytokinesis based on the observation that PLK1 interacts and co-localizes with a kinesin related motor protein (CHO1/MKLP-1) at the interzone during anaphase and the mid-body during telophase and cytokinesis.
Evidence suggests that BRCA2 is a substrate of PLK1 both in response to DNA damage and during normal cell cycle progression. This suggests a role for PLK1 in regulating DNA damage repair.
Other studies have shown that the loss of PLK1 expression can induce pro-apoptotic pathways and inhibit growth.
Based on yeast and murine studies of meiosis, human PLK1 may also have a regulatory function in meiosis. S. cerevisiae polo kinase CDC5 is required to phosphorylate and remove meiotic cohesion during the first cell division. In CDC5 depleted cells, kinetochores are bioriented during meiosis I, and Mam1, a protein essential for coorientation, fails to associate with kinetochores. CDC5 is believed to have roles in sister-kinetochore coorientation and chromosome segregation during meiosis I..

Homology

P.troglodytes: PLK1, polo-like kinase, XP_510879.1, 735 aa
M.musculus: Plk1, polo-like kinase 1 (Drosophila), NP_035251.2, 603 aa
R.norvegicus: Plk1, polo-like kinase 1 (Drosophila), NP_058796.1, 603 aa
D.melanogaster: polo, polo, NP_524179.2, 576 aa
C.elegans: plk-1 PoLo Kinase, NP_741243.1, 649 aa
S.cerevisiae: CDC5, NP_013714.1, 705 aa

Implicated in

Note
Increased PLK1 levels are detected in a variety of cancers.
Disease
Increased PLK1 transcript has been detected in a variety of tumor types including esophageal, head and neck squamous cell, liver, lung and breast carcinomas. Immunohistochemical studies also demonstrate increased PLK1 protein levels in melanomas, breast, ovarian, prostate cancers, and head, neck squamous cell carcinomas.
Prognosis
Statistically significant correlations between increased PLK1 expression and decreased patient survival suggest that PLK1 is a negative prognostic indicator for some types of cancer. For example,
  • In prostate cancer, PLK1 overexpression is linked to higher tumor grades
  • In non-Hodgkins lymphomas, PLK1 overexpression reflect malignancy potentials
  • In hepatoblastomas, ovarian, colorectal cancers and melanomas, PLK1 overexpression suggests PLK1 to be a poor-prognostic indicator.
  • Oncogenesis
    Oncogenic properties of PLK1 are believed to be due to its role in driving cell cycle progression. Supporting evidence comes from the overexpression studies of PLK1 in NIH3T3 cell line. These cells become capable of forming foci and growing in soft agar and more importantly, these cells can form tumors in nude mice due to PLK1 overexpression.

    PLK1 has also been linked to known pathways that are altered during the neoplastic transformation. Retinoblastoma tumor suppressor (RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNF chromatin remodeling complex dependent manner. In case of RB inactivation, PLK1 expression seems to be deregulated. This new finding suggests that PLK1 may be a target of the retinoblastoma tumor suppressor (RB) pathway.

    Moreover, PLK1 seems to be involved in the tumor suppressor p53 related pathways. Evidence suggests that PLK1 can inhibit transactivation and pro-apoptotic functions of p53 function by physical interaction and phosphorylation.

    In addition to PLK1s role in normal cell cycle regulation, its connection to such known tumor suppressors may be crucial for the tumorigenesis processes.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    150240212004Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation.Ando K et al
    99143741998GFP tagging reveals human Polo-like kinase 1 at the kinetochore/centromere region of mitotic chromosomes.Arnaud L et al
    93702991997The mouse Plk gene: structural characterization, chromosomal localization and identification of a processed Plk pseudogene.Clay FJ et al
    156408422005Polo-like kinases and oncogenesis.Eckerdt F et al
    98696301998Polo-like kinases: a team that plays throughout mitosis.Glover DM et al
    79621931994Cell cycle analysis and chromosomal localization of human Plk1, a putative homologue of the mitotic kinases Drosophila polo and Saccharomyces cerevisiae Cdc5.Golsteyn RM et al
    151054332004Hierarchical requirement of SWI/SNF in retinoblastoma tumor suppressor-mediated repression of Plk1.Gunawardena RW et al
    80185571994Cloning and characterization of human and murine homologues of the Drosophila polo serine-threonine kinase.Hamanaka R et al
    154699842004Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1.Hansen DV et al
    111244272000Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes.Harris PL et al
    121354662002Expression of polo-like kinase (PLK1) in thin melanomas: a novel marker of metastatic disease.Kneisel L et al
    79025331993Cell cycle- and terminal differentiation-associated regulation of the mouse mRNA encoding a conserved mitotic protein kinase.Lake RJ et al
    89910841996Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes.Lane HA et al
    126638162003Role of Polo-like kinase CDC5 in programming meiosis I chromosome segregation.Lee BH et al
    85242821995Plk is an M-phase-specific protein kinase and interacts with a kinesin-like protein, CHO1/MKLP-1.Lee KS et al
    146474132004Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression.Lee M et al
    128150532003M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex.Lin HR et al
    147345342004Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cells.Lindon C et al
    127327292003Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells.Liu X et al
    151990972004Molecular interactions of Polo-like-kinase 1 with the mitotic kinesin-like protein CHO1/MKLP-1.Liu X et al
    156218052005Expression of Polo-Like Kinase (PLK1) in non-Hodgkin's lymphomas.Mito K et al
    91772831997Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase.Smith MR et al
    127084892003Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal cancers.Takahashi T et al
    156408442005Polo-like kinases (Plks) and cancer.Takai N et al
    124937542003Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody.Tsvetkov L et al
    151760532004Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades.Weichert W et al
    156408412005Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues.Winkles JA et al
    111861702000Polo-like kinase: a novel marker of proliferation: correlation with estrogen-receptor expression in human breast cancer.Wolf G et al
    152210052004Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas.Yamada S et al

    Other Information

    Locus ID:

    NCBI: 5347
    MIM: 602098
    HGNC: 9077
    Ensembl: ENSG00000166851

    Variants:

    dbSNP: 5347
    ClinVar: 5347
    TCGA: ENSG00000166851
    COSMIC: PLK1

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000166851ENST00000300093P53350
    ENSG00000166851ENST00000567897I3L2H5
    ENSG00000166851ENST00000568568I3L309
    ENSG00000166851ENST00000570220I3L387

    Expression (GTEx)

    0
    50
    100
    150

    Pathways

    PathwaySourceExternal ID
    Cell cycleKEGGko04110
    Progesterone-mediated oocyte maturationKEGGko04914
    Cell cycleKEGGhsa04110
    Progesterone-mediated oocyte maturationKEGGhsa04914
    Oocyte meiosisKEGGko04114
    Oocyte meiosisKEGGhsa04114
    FoxO signaling pathwayKEGGhsa04068
    Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
    Cilium AssemblyREACTOMER-HSA-5617833
    Anchoring of the basal body to the plasma membraneREACTOMER-HSA-5620912
    Signal TransductionREACTOMER-HSA-162582
    Signaling by Rho GTPasesREACTOMER-HSA-194315
    RHO GTPase EffectorsREACTOMER-HSA-195258
    RHO GTPases Activate ForminsREACTOMER-HSA-5663220
    Cell CycleREACTOMER-HSA-1640170
    Cell Cycle, MitoticREACTOMER-HSA-69278
    Mitotic G2-G2/M phasesREACTOMER-HSA-453274
    G2/M TransitionREACTOMER-HSA-69275
    Cyclin A/B1 associated events during G2/M transitionREACTOMER-HSA-69273
    Regulation of PLK1 Activity at G2/M TransitionREACTOMER-HSA-2565942
    Polo-like kinase mediated eventsREACTOMER-HSA-156711
    Centrosome maturationREACTOMER-HSA-380287
    Recruitment of mitotic centrosome proteins and complexesREACTOMER-HSA-380270
    Loss of proteins required for interphase microtubule organization from the centrosomeREACTOMER-HSA-380284
    Loss of Nlp from mitotic centrosomesREACTOMER-HSA-380259
    M PhaseREACTOMER-HSA-68886
    Mitotic ProphaseREACTOMER-HSA-68875
    Golgi Cisternae Pericentriolar Stack ReorganizationREACTOMER-HSA-162658
    Condensation of Prophase ChromosomesREACTOMER-HSA-2299718
    Nuclear Envelope BreakdownREACTOMER-HSA-2980766
    Activation of NIMA Kinases NEK9, NEK6, NEK7REACTOMER-HSA-2980767
    Mitotic PrometaphaseREACTOMER-HSA-68877
    Resolution of Sister Chromatid CohesionREACTOMER-HSA-2500257
    Mitotic Metaphase and AnaphaseREACTOMER-HSA-2555396
    Mitotic Metaphase/Anaphase TransitionREACTOMER-HSA-68881
    Mitotic AnaphaseREACTOMER-HSA-68882
    Separation of Sister ChromatidsREACTOMER-HSA-2467813
    Mitotic Telophase/CytokinesisREACTOMER-HSA-68884
    Regulation of mitotic cell cycleREACTOMER-HSA-453276
    APC/C-mediated degradation of cell cycle proteinsREACTOMER-HSA-174143
    Regulation of APC/C activators between G1/S and early anaphaseREACTOMER-HSA-176408
    Phosphorylation of Emi1REACTOMER-HSA-176417
    Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteinsREACTOMER-HSA-176814
    Phosphorylation of the APC/CREACTOMER-HSA-176412
    APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1REACTOMER-HSA-174178
    The role of GTSE1 in G2/M progression after G2 checkpointREACTOMER-HSA-8852276
    AURKA Activation by TPX2REACTOMER-HSA-8854518

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    145320052003The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain.291
    186150132008Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery.286
    125956922003Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates.267
    185662902008Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry.239
    186625412008The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint.180
    119317602002The dissociation of cohesin from chromosomes in prophase is regulated by Polo-like kinase.161
    153502232004Polo-like kinase-1 controls recovery from a G2 DNA damage-induced arrest in mammalian cells.144
    172182582007PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint.140
    191604882008Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression.138
    127327292003Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells.135

    Citation

    Ayse Elif Erson ; Elizabeth M. Petty

    PLK1 (polo-like kinase 1 (Drosophila))

    Atlas Genet Cytogenet Oncol Haematol. 2005-04-01

    Online version: http://atlasgeneticsoncology.org/gene/41747/plk1