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Overexpression of HMGA1a oncoprotein induces aberrant exon 5 skipping of the presenilin-2 pre-mRNA, found almost exclusively in sporadic Alzheimer's disease. Ohe and Mayeda (p. 2220-2228) have elucidated a definitive molecular mechanism of this aberrant splicing. HMGA1a binding to a specific HMGA1a-binding site adjacent to the 5′ splice site stably traps U1 snRNP and impairs dissociation of U1 snRNP from the 5′ splice site, which causes a defect in normal exon definition. Intriguingly, the shared mechanism triggered by aberrant U1 snRNP binding, which is evolutionally conserved from yeast to humans, modulates the posttranscriptional events, leading to significant physiological and medical phenotypes.
SENP2 is one of the SUMO-specific proteases, and little was known about its physiological function. Chung et al. (p. 2135-2146) revealed that SENP2 plays an important role in adipogenesis. Expression of SENP2 is markedly increased at the early stage of adipogenesis. Knockdown of SENP2 strongly inhibits adipogenesis, with a marked reduction of C/EBPβ, peroxisome proliferator-activated receptor γ, and C/EBPα in cultured cells and also attenuates adipogenesis of implanted preadipocytes in vivo. Importantly, SENP2 stabilizes C/EBPβ by desumoylation and C/EBPβ overexpression reverses the inhibitory effect of SENP2 knockdown on adipogenesis. These results suggest that SENP2 controls adipogenesis by desumoylation and stabilization of C/EBPβ.
Dendrite formation is critical for normal mammalian brain function including cognition and memory formation. The bone morphogenetic protein (BMP) family of secreted factors regulate neuronal differentiation, and BMP7, in particular, induces dendrite formation. Podkowa et al. (p. 2241-2250) provide the exciting advance that BMP receptor II (BMPRII) acts as a scaffold to bind the microtubule cytoskeleton regulators c-Jun kinases (JNKs) at tips of dendrites to promote dendritogenesis. Activation and binding of JNKs to BMPRII are required for BMP7-induced microtubule stabilization and dendrite formation in primary cortical neurons. This work thus shows that BMP7 signaling via BMPRII is a critical regulator of microtubule dynamics in neurons.
Par1b/MARK2 is an evolutionarily conserved kinase that regulates cell polarity, which is associated with axon specification in mammalian neurons. Yoshimura et al. (p. 2206-2219) report that GAKIN/KIF13B, a kinesin-like motor protein, is a crucial substrate for Par1b. GAKIN/KIF13B accumulates specifically at axon tips, and overexpression of GAKIN/KIF13B by itself induces the formation of extra axons, which is inhibited by the coexpression of Par1b via its kinase activity. The extra-axon phenotype caused by Par1b knockdown is suppressed by GAKIN/KIF13B knockdown, thus placing the GAKIN/KIF13B function downstream of Par1b. These results reveal that GAKIN/KIF13B is a key intermediate linking Par1b to neuronal polarity.
CENP-A plays a crucial role in organizing kinetochore chromatin for precise chromosome segregation. Maehara et al. (p. 2264-2278) show that the level of CENP-A protein is markedly reduced in senescent human cells and that forced reduction of CENP-A drives normal human diploid fibroblasts into a senescent state in a p53-dependent manner. In the absence of p53, CENP-A reduction failed to block cell division and led to marked elevation in the levels of chromosome missegregation. CENP-A depletion-associated senescence may be a self-defense mechanism to suppress the otherwise catastrophic impact upon genome integrity that would arise from kinetochore dysfunction following certain types of stress.