Department of  Neurosurgery
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Current Research — Kim Lab

The Kim Laboratory has two research concentrations:

  • Glioblastoma multiforme
  • Ubiquitination in brain development and disease

Glioblastoma multiforme

Glioblastoma multiforme

Glioblastoma multiforme is the most common malignant brain tumor in adults. Despite aggressive surgical resection, chemotherapy and radiation therapy, this disease remains challenging with no cure. A subpopulation of glioblastoma cells called cancer stem cells drives tumor growth and has been implicated in the development of treatment resistance and tumor recurrence. Little is known about the molecular mechanisms that control key features of cancer stem cell biology, including invasiveness and multipotency, characteristics that have striking similarities to events in early neural development. The elucidation of these mechanisms is critical for our understanding of brain cancer behavior and will also advance our knowledge of normal nervous system development. The long-term goal of my laboratory is to leverage these insights for the rational design of novel strategies against this formidable tumor.

Generation of glioblastoma stem cells

Generation of glioblastoma stem cells
Figure 2. Experimental design for the investigation of glioblastoma stem cell biology.
Generation of glioblastoma stem cells
Figure 3. Glioblastoma stem cells derived from patient tumor grown in monolayer. Low passage number glioblastoma stem cells were subjected to phase contrast microscopy (left) as well as anti-Nestin (green, top right) and anti-Sox2 (red, bottom right) immunofluorescence. Immunofluorescence images were merged with DAPI nuclear dye images (blue).

Ubiquitination in brain development and disease

Ubiquitination in brain development and disease
Figure 1.Diagram of the cellular biochemistry and biology of ubiquitination. E1 = ubiquitin-activating enzyme; E2 = ubiquitin-conjugating enzyme; DUB = deubiquitinase; Ub = ubiquitin.

Ubiquitination is a major post-translational modification that governs a diverse array of normal biological processes, from developmental events to homeostatic processes. Covalent attachment of ubiquitin to specific substrate proteins results in protein degradation or alteration in protein function/localization. Abnormalities in ubiquitin signaling lead to protein derangements and in certain contexts to human diseases, including tumorigenesis.

Among E3 ligases, the Anaphase-Promoting Complex (APC) is evolutionarily conserved and critical for cell cycle transitions. Via binding of coactivator Cdc20, the APC drives sister chromatid separation at anaphase and mitotic exit through polyubiquitination of cell cycle substrates, which are subsequently degraded by the proteasome.

Remarkably, core APC subunits are highly expressed in the mammalian brain, suggesting functions for Cdc20-APC beyond cell division. Recently, I have discovered Cdc20-APC is essential for neuronal morphogenesis in diverse neurons of the brain in culture and in the rodent cerebellar cortex in vivo.

Ubiquitination figure 2
Figure 2.Major mitotic regulator and E3 ligase Anaphase-Promoting Complex is essential for neuronal morphogenesis. A. Lysates from COS cells transfected with indicated plasmids were subjected to immunoblotting. B. Cerebellar granule neurons from P6 rats were transfected with indicated plasmids along with GFP and processed for GFP immunofluorescence. Arrow = dendrite; arrowhead = axon. C. Neurons were transfected with indicated plasmids and processed as in B. Morphometric analysis was performed (total dendrite length + SEM). D. Left: Cdc20 immunofluorescence (red) in neurons revealed a centrosomal localization (arrow). Right: Merge with Hoechst nuclear label.

Figure reprintedwith permission from Elsevier. REF:A.H. Kim, S.V. Puram, P.M. Bilimoria, S. Keough, M. Wong, D. Rowitch, and A. Bonni. A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons. Cell. 136(2):322-336. 2009.