PLK1

Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an is_associated_with::enzyme that in humans is encoded by the PLK1 (is_associated_with::polo-like kinase 1) is_associated_with::gene.

Structure
PLK1 consists of 603 is_associated_with::amino acids and is 66kDa. In addition to the is_associated_with::N-terminus is_associated_with::kinase domain, there are two conserved polo-box regions of 30 amino acids at the is_associated_with::C-terminus. Kinase activity is regulated at least in part, by the polo-boxes that are functionally important for both is_associated_with::auto-inhibition and is_associated_with::subcellular localization.

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

Cell cycle regulation
Plk1 is an early trigger for G2/M transition. Plk1 supports the functional maturation of the centrosome in late G2/early is_associated_with::prophase and establishment of the bipolar spindle. Plk1 phosphorylates and activates cdc25C, a is_associated_with::phosphatase that dephosphorylates and activates the cyclinB/is_associated_with::cdc2 complex. Plk phosphorylates and activates components of the is_associated_with::anaphase-promoting complex (APC). The APC, which is activated by Fizzy-Cdc20 family proteins, is a cell cycle is_associated_with::ubiquitin-protein ligase (E3) that degrades is_associated_with::mitotic cyclins, chromosomal proteins that maintain cohesion of is_associated_with::sister chromatids, and is_associated_with::anaphase inhibitors. Abnormal spindle (Asp), a Polo kinase substrate, is a is_associated_with::microtubule-associated protein essential for correct behavior of is_associated_with::spindle poles and M-phase microtubules. Plk1 localizes to the central region of the spindle in late mitosis and associates with is_associated_with::kinesin-like protein CHO1/MKLP1. The homologous is_associated_with::motor protein in is_associated_with::Drosophila is the pavarotti gene product (PAR).

Studies have shown that the loss of PLK1 expression can induce is_associated_with::pro-apoptotic pathways and inhibit growth. Based on yeast and murine studies of is_associated_with::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 is_associated_with::chromosome segregation during meiosis I.

Role in tumorigenesis
Plk1 is considered a is_associated_with::proto-oncogene, whose is_associated_with::overexpression is often observed in is_associated_with::tumor cells. is_associated_with::Aneuploidy and is_associated_with::tumorigenesis can also result from is_associated_with::centrosome abnormality, particularly centrosome amplification defects. Centrosome duplication and maturation regulated by Plk1 occurs from late is_associated_with::S phase to prophase. Abnormal centrosome amplification may lead to is_associated_with::multipolar spindles and results in unequal segregation of chromosomes.Plk1 overexpression also increases the centrosome size and/or centrosome number, which will also lead to improper segregation of chromosomes, aneuploidy, and tumorigenesis.

Oncogenic properties of PLK1 are believed to be due to its role in driving is_associated_with::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 is_associated_with::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 is_associated_with::neoplastic transformation. is_associated_with::Retinoblastoma tumor suppressor (RB) pathway activation results in the repression of PLK1 promoter in a SWI/SNF is_associated_with::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 is_associated_with::transactivation and pro-apoptotic functions of p53 function by physical interaction and is_associated_with::phosphorylation.

Clinical significance
PLK1 is being studied as a target for is_associated_with::cancer drugs. Many colon and is_associated_with::lung cancers are caused by K-RAS mutations. These cancers are dependent on PLK1. When PLK1 expression was silenced with is_associated_with::RNA interference in is_associated_with::cell culture, K-RAS cells were selectively killed, without harming normal cells.

Interactions
PLK1 has been shown to interact with:


 * is_associated_with::CHEK2,
 * is_associated_with::NUDC,
 * is_associated_with::PIN1,
 * is_associated_with::PSMA3,
 * is_associated_with::PSMA5,
 * is_associated_with::PSMA6,
 * is_associated_with::PSMA7,
 * is_associated_with::PSMB3, and
 * is_associated_with::TSC1.

Structural analysis has been used to explain the broad specificity of PLK1.