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199 A Hybrid Genome-Kinome High-Throughput Screen Reveals Novel Mitotic Tumor Suppressor Signaling Axis
  1. G Nalepa1,
  2. J Barnholtz-Sloan2,
  3. AS Lehmann1,
  4. FC Yang1,
  5. J Renbarger1,
  6. DW Clapp1
  1. 1Indiana University School of Medicine, Indianapolis, IN
  2. 2Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH, USA

Abstract

Faithful cell division maintains genomic stability and prevents cancer. Our cells employ well-orchestrated signaling cascades to ensure meticulous segregation of the genome during mitosis. Failure of these checkpoint mechanisms jeopardizes genome integrity and promotes evolution of cancer cells.

Here, we took a systems biology approach to characterize phosphatases regulating mitosis. We performed a genome-wide RNAi screen targeting all human phosphatases.

We discovered several novel mitotic phosphatases, including CDKN3, and we have shown that CDKN3 inactivates cyclin-dependent kinases at the exit from mitosis by dephosphorylating Thr-161 of CDC2. We demonstrated that CDKN3 and CDC2 co-localize on centrosomes during mitosis and that loss of CDKN3 disrupts centrosome maintenance. We analyzed a phosphoproteome landscape of

CDKN3-deficient cells to reveal that CDKN3 knockdown leads to abnormal phosphorylation of multiple downstream cell cycle proteins, including CKβ. We have shown that CKβ phosphorylated at Ser-209 regulates the spindle checkpoint and localizes to centrosomes during mitosis. We confirmed that CDKN3 is required for mitosis in primary human brain stem cells, and we found that CDKN3 is lost in the glioblastoma multiforme brain tumors.

In summary, we have discovered a novel CDKN3/CDC2/CKβ tumor suppressor signaling axis. Our findings have diagnostic and therapeutic importance in cancer. Our discoveries enhance our comprehension of the cross-talk between mitotic phosphorylation cascades that maintain genomic stability. This signaling axis is a viable anti-cancer target in glioblastoma multiforme and other malignancies. Pre-clinical and clinical trials of small molecules targeting this signaling axis may lead to discoveries of novel anti-cancer chemotherapy strategies.

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