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Bub1b

Official Full Name
BUB1 mitotic checkpoint serine/threonine kinase B
Background
The Mitotic Checkpoint Complex (MCC), which contains Bub1, Bub1b, Bub3, Mad2, and Cdc20, controls chromosome segregation and monitors kinetochore-microtubule interactions (1). During mitosis, the MCC complex inhibits the ubiquitin ligase activity of the A
Synonyms
BUB1B; budding uninhibited; budding uninhibited by benzimidazoles 1 (yeast homolog), beta; mitotic checkpoint serine/threonine-protein kinase BUB1 beta; Bub1A; BUBR1; MAD3L; SSK1; mitotic checkpoint kinase MAD3L; MAD3/BUB1-related protein kinase; hBUBR1; BUB1beta; BUB1 mitotic checkpoint serine/threonine kinase B; budding uninhibited by benzimidazoles 1 homolog beta; BUB1 budding uninhibited by benzimidazoles 1 homolog beta

Recent Research Progress

The mitotic checkpoint serine/threonine kinase B (BUB1B) is a mammalian homolog of yeast Mad3, but differs significantly because BUB1B has a kinase domain that is not found in Mad3. A recent study showed that complete loss of BUB1B in mouse germline led to early embryonic death. In addition, BUB1B (haploid deficiency) mice illustrated increased megakaryocyte production and increased chromosomal instability, as well as susceptibility to cancer. Besides, decreased levels of BUB1B or inhibition of BUB1B kinase activity in human cancer cells result in massive chromosome loss and apoptotic cell death.

BUB1B and Lung adenocarcinoma

Lung adenocarcinoma is often found as a metastatic disease with a very poor prognosis. However, the mechanism of tumor progression in lung adenocarcinoma is unclear. Recent studies have found that knockdown of BUB1B/BUBR1, a key mitotic checkpoint protein, significantly suppressed anchor-independent growth of lung adenocarcinoma cell lines. In a mouse model study of allogeneic and tail veins, BUB1B suppression inhibits primary tumor growth and reduces metastasis to the lungs and lymph nodes, leading to prolonged survival in tumor prevention and tumor intervention settings. Mechanistic studies have revealed that knockdown of BUB1B made cells susceptible to anoikis. The N-terminal region of the BUB1B and the GLEBS domain are both essential for anchorage-independent growth and anoikis resistance, while the kinase domain is less important. Overexpression of BUB1B is associated with disease progression and poor survival in human lung adenocarcinoma patients. Taken together, these data reveal a novel function of BUB1B in mediating non-adherent survival and growth, thereby promoting lung adenocarcinoma transmission during lung metastasis. Thus, targeting BUB1B can provide potential therapeutic benefits in inhibiting metastasis and prolonging survival in patients with lung adenocarcinoma.

BUB1B and MM

Multiple myeloma (MM) is the second most common hematopoietic malignancy characterized by plasma cell proliferative disorders. Recently, studies have discovered that the expression of BUB1B was significantly increased in high-risk myeloma patients, especially in the proliferation of the most invasive myeloma genetic subpopulation. Increased BUB1B expression promotes MM cell proliferation. Mechanistic studies indicated that BUB1B expression was highly correlated with the expression of CDC20 and CCNB1/2 in MM cells (Figure 1), resulting in increased proliferation of MM cells. Therefore, BUB1B may be a potential target for MM treatment, especially for high-risk MM patients.

Figure 1. An illustration of BUB1B/CDC20/CCNB1/2 axis working model (Ye Yang, et al. Med Oncol, 2015)

BUB1B and GBM

There is growing evidence that BUB1B plays a key role in many types of cancer. However, the biological function and molecular regulation mechanism of BUB1B in glioblastoma (GBM) remain unclear. Recent studies have identified that BUB1B expression was enriched in GBM tumors and was required for tumor proliferation both in vitro and in vivo. Clinically, BUB1B expression is related to poor prognosis in GBM patients, and BUB1B-dependent radioresistance in GBM is reduced by shRNA targeting BUB1B. Mechanically, the forkhead box protein M1 (FOXM1) regulates BUB1B expression by binding and subsequent activation of the BUB1B promoter transcription. Therapeutically, FOXM1 inhibitors attenuate GBM tumorigenesis and radiation resistance both in vitro and in vivo. In conclusion, BUB1B promotes tumor proliferation and induces radioresistant resistance to GBM, suggesting that BUB1B may be a potential therapeutic target for GBM.

In short, BUB1B has been shown to play an important role in tumor proliferation and is associated with poor prognosis in a variety of cancers, including breast, gastric, colorectal and prostate cancers. In addition, the polymorphism of BUB1B may contribute to the risk of tumorigenesis and tumor development. Therefore, further investigation of large populations and people of different ethnicities to determine their clinical utility is very valuable.

References:

  1. Chen Honglin, et al. Requirement for BUB1B/BUBR1 in tumor progression of lung adenocarcinoma. Genes & cancer, 2016, 6(3-4):106-18
  2. Ye Yang, et al. BUB1B promotes multiple myeloma cell proliferation through CDC20/CCNB axis, Med Oncol, 2015, 32:81
  3. Qing Ma, et al. The FOXM1/BUB1B signaling pathway is essential for the tumorigenicity and radioresistance of glioblastoma. Oncology Reprots, 2017, 38:3367-3375
  4. Ochiai H, et al. TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome. Proceedings Of The National Academy Of Sciences Of The United States Of America, 2014, 111(4):1461-1466
  5. Petra Hudler, et al. Association between polymorphisms in segregation genes BUB1B and TTK and gastric cancer risk. Radiol Oncol, 2016, 50(3):297-307.
  6. Maki Kato, et al. PCS/MVA syndrome caused by an Alu insertion in the BUB1B gene. Official journal of the Japan Society of Human Genetics, 2017, 4:17021;
  7. Marc-Manuel Hahn, et al. Prevalence of Germline Mutations in the Spindle Assembly Checkpoint Gene BUB1B in Individuals with Early-Onset Colorectal Cancer. Chromosomes &Cancer, 2016, 55:855–863

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