Disease relevance of Bub1

• This report demonstrates that Bub1 and BubR1 mutant proteins from Brca2-/- thymic lymphomas have defects in the phosphorylation and kinetochore localization after spindle damage [1].
• Whereas the exact details of this mechanism remain unclear, our novel findings raise the possibility of exploiting Bub1 as a new therapeutic target in the treatment of prostate cancer, the most common cancer in adult men in North America. (Mol Cancer Res 2006;4(12):957-69) [2].

High impact information on Bub1

• Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage [3].
• In Xenopus oocytes, the spindle assembly checkpoint (SAC) kinase Bub1 is required for cytostatic factor (CSF)-induced metaphase arrest in meiosis II [4].
• Our data indicate that mAsh1 negatively regulates the cell cycle (e.g., via enhanced Cdkn2d, Bub1 expression), promotes differentiation (e.g., through effects on cAMP), and enhances survival by inhibiting apoptosis [5].
• We report that, despite high-level expression of dominant-negative Bub1 (Bub1DN), a protein known to inhibit spindle checkpoint activity in cultured cells, thymocytes show no evidence of spindle checkpoint impairment [6].
• Differences between the Bub1 sequences suggest that the two proteins may have different substrate specificities and that Bub1b alone has a putative "destruction" box that can target proteins for degradation by proteosomes during mitosis [7].

Chemical compound and disease context of Bub1

• In particular, the spindle checkpoint component Bub1 was persistently up-regulated from early to advanced androgen-independent prostate cancer lesions [2].

Biological context of Bub1

• This cell cycle-dependent expression explains the tissue distribution and the abundance of Bub1 mRNAs in rapidly dividing cell lines [7].
• Thus, the mutations of Bub1 and BubR1 found in Brca2- mutant mice indeed are responsible for the chromosome instability in Brca2-mutated tumors [1].
• Impaired phosphorylation and mis-localization of Bub1 and BubR1 are responsible for the defective mitotic checkpoint function in Brca2-mutant thymic lymphomas [1].
• Bub1 prevents chromosome misalignment and precocious anaphase during mouse oocyte meiosis [8].
• Bub1 Up-Regulation and Hyperphosphorylation Promote Malignant Transformation in SV40 Tag-Induced Transgenic Mouse Models [2].

Anatomical context of Bub1

• Northern blots of normal tissues show that mouse Bub1a and Bub1b genes are expressed in thymus and spleen, but not in nondividing tissues [7].
• In addition, we depicted the localization dynamics of Bub1 in response to spindle damage and its relationship with microtubules and chromosomes, providing further evidence for Bub1's role as a spindle checkpoint protein [8].

Associations of Bub1 with chemical compounds

• Bub1 suppression also overrode the checkpoint-dependent cell cycle arrest provoked by a low dosage of nocodazole [8].

Regulatory relationships of Bub1

• In the present study we blocked the function of Bub1 during meiosis by microinjecting anti-Bub1 specific antibody into cytoplasm of mouse oocytes, and found that depletion of Bub1 induced evident cyclin B degradation and precocious anaphase onset [8].

Other interactions of Bub1

• Thymic lymphomas from Brca2-mutant mice harbor mutations in p53, Bub1, and BubR1, which function as mitotic checkpoint proteins [1].

Analytical, diagnostic and therapeutic context of Bub1

• Consistent with a spindle checkpoint defect, flow cytometry experiments indicate that advanced androgen-independent prostate cancer tumors exhibit aneuploidy, along with up-regulation of levels of both Bub1 mRNA and Bub1 protein or hyperphosphorylation [2].

References