By means of a variety of mechanisms, Akt downregulates p27, a vital Cdk inhibitor that halts cells in lateG1 till cells are ready for DNA synthesis . On top of that, the PI3K?Akt pathway also regulates the transition at G2/M. Either PI3K inhibitors or the absence of Akt in Akt1-null ES cells had been reported to induce a delay in G2/M transition . The PI3K?Akt pathway continues to be shown to regulate mitotic entry additionally to its mitogenic functions at the G1/S transition. Inhibition of PI3K outcomes within a delay during the progression as a result of G2/M, which might be rescued by overexpressing Akt . PTEN-null ES cells have been proven to transit faster via the G2/M phase . Overexpressing a dominant-negative mutant of Akt also arrests cells in G2/M . Lastly, PI3K?Akt pathway regulates mitotic entry through controlling the timing of Cdc2 activation .
Wee1 and Myt1 are two kinases that phosphorylate Cdc2 at Thr14/ Tyr15 and inhibit Cdc2 kinase action. Akt phosphorylates and downregulates Myt1 with the G2/M boundary . Also, Akt was shown to phosphorylateWEE1Hu MP-470 at Ser642, which in turn provides the binding internet site for 14-3-3?. This 14-3-3? binding translocates WEE1Hu into the cytoplasm and, thus, prevents its inhibitory phosphorylation on Cdc2 . Akt also prevents Plk1 degradation by means of CHFR and promotes mitotic entry below normal circumstances and immediately after DNA injury . Aurora kinases are serine/threonine kinases that regulate mitotic events, ranging from centrosome maturation, mitotic spindle formation, chromosome segregation to cytokinesis . The three members of Aurora kinase household in metazoans share in depth construction and sequence similarities .
Nevertheless, they present distinct localizations and functions during mitosis. Aurora A localizes to centrosomes and it is essential for centrosome duplication and maturation . Overexpression of Aurora A leads to genomic instability and neoplastic transformation, demonstrating that Aurora A is a bonafide oncogene . Cells depleted of Aurora A by siRNA are arrested at mitosis Synephrine and display a G2 delay in synchronized cells . Aurora B is localized to centromeres in early mitosis, relocates to the central spindle in anaphase along with the spindle midzone throughout telephase, and ultimately migrates for the midbody for the duration of cytokinesis . Aurora B functions like a chromosome passenger protein involved in chromosome condensation, kinetochore?microtubule attachment, chromosome alignment in metaphase, and midbody function for the duration of cytokinesis .
Aurora C is additionally linked to the centrosomes, but its function in mitosis is not properly defined .