CtBPs promote mitotic fidelity through their activities in the cell nucleus

Abstract

CtBPs form NADH-sensitive chromatin-modifying complexes, which link cellular metabolism to gene transcription. They also function in the cytoplasm to regulate Golgi fissioning; their inhibition can consequently cause a Golgidependent checkpoint in G 2 . We have recently identified a novel role of CtBPs in the maintenance of mitotic fidelity; inhibition of CtBP synthesis resulting in reduced association of aurora B with mitotic chromatin and aberrant segregation of chromosomes. Here, we demonstrate that it is the interaction of CtBPs with transcriptional regulators and/or chromatin-modifying enzymes in the cell nucleus, rather than their role in Golgi fission, which is critical for the maintenance of mitotic fidelity.

Fanconi anemia proteins interact with CtBP1 and modulate the expression of the Wnt antagonist Dickkopf-1

“…This is consistent with previous reports showing that CtBP1 is involved in mitotic fidelity, including chromosome pairing during cellular division. 18,31 Collectively, our results suggest that CtBP1-depleted cells lead to defects that characterize cells from FA patients.…”

“…[17][18][19][20] Both are widely expressed throughout development and are often expressed in overlapping patterns, which leads to functional redundancy. 21 CtBPs have at least two distinct roles: in the cytoplasm, they function in the Golgi tubule-fissioning machinery; in the nucleus, they cooperate with DNA-binding transcription factors, such as Wnt/b-catenin/T-cell factor (TCF), in recruiting chromatin-modifying enzymes to promoters to achieve transcriptional corepression.…”

p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators

“…To investigate which activities of CtBPs were responsible for their p53-suppressing activity, we used our approach of microinjection of dominant-negative fragments of CtBPs to dissect CtBP function (56). Microinjection of MCF-7 GLU cells with an N-terminal fragment of CtBP2 (CtBP DN ) designed to be targeted to the cell nucleus and disrupt the interaction of CtBPs with multiple protein partners including HDM2, resulted in the accumulation of p53 protein in most of the injected nuclei ( Fig.…”

Glycolysis, via NADH‐dependent dimerisation of CtBPs, regulates hypoxia‐induced expression of CAIX and stem‐like breast cancer cell survival

“…Furthermore, given the evidence using the CtBP2 G189A mutant, which suggested a role for NADH-dependent CtBP dimerisation in the regulation of CAIX expression, a function that is regulated by glycolysis, we specifically set out to further test this aspect of CtBP regulation in the control of CAIX expression and SCLC cell biology. We have previously developed an approach of microinjection of fragments of CtBP proteins to act as dominant negative inhibitors of specific functions [45,46], including CtBP DD , which encompasses the dehydrogenase/dimerisation domain and thus competes for dimerisation of endogenous CtBP dimers [46]. We therefore constructed an inducible system where the expression of V5-tagged CtBP DD could be switched on by doxycycline in stably transduced MCF-7 cells.…”

“…This, and their higher affinity for NADH over NAD + , means that they function as regulators of transcription in response to altered rates of glycolytic flux [38]. Glycolysis and CtBP-dependent transcriptional regulation impacts on multiple cellular phenotypes involved in cancer development, including epithelial-to-mesenchymal transition and hypoxia-induced cell migration [39][40][41], metastasis [42], resistance to cell death [41], suppression of DNA repair [40,43,44], maintenance of the fidelity of mitosis [45,46], resistance to cell cycle inhibition [47], p53-dependent stress responses [48] and the acquisition of stem cell-like phenotypes [35,40,49]. Elevated CtBP expression is also associated with poor prognosis in a wide range of solid tumours, including breast cancer [40].…”