Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.

The mitochondrial inner membrane contains a large protein complex that functions in inner membrane organization and formation of membrane contact sites. The complex was variably named the mitochondrial contact site complex, mitochondrial inner membrane organizing system, mitochondrial organizing structure, or Mitofilin/Fcj1 complex. To facilitate future studies, we propose to unify the nomenclature and term the complex “mitochondrial contact site and cristae organizing system” and its subunits Mic10 to Mic60.

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Background: Functional characterization of a novel mitochondrial protein, CHCM1/CHCHD6, is reported. Results: CHCM1 interacts with Mitofilin, DISC1, and CHCHD3, and its deficiency leads to severe defects in mitochondrial cristae morphology, reduction in cell growth, ATP production, and oxygen consumption. Conclusion: CHCM1/CHCHD6 is a novel player linked to mitochondrial cristae morphology. Significance: Results provide valuable insights into molecular events controlling the structural integrity and biogenesis of mitochondrial cristae.

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p53-mediated apoptosis involves multiple mechanisms. A number of p53-regulated apoptosis-related genes have been identified. Some of these genes encode proteins that are important in controlling the integrity of mitochondria while the others code for membrane death receptors. p53 may also induce apoptosis by interfering with the growth factor-mediated survival signals. Although the transactivation-deficient p53 can induce apoptosis, evidence suggests that both the transcription-dependent and independent functions are needed for full apoptotic activity. p73 and p63 are two other members of the p53 family that show homology to p53 in their respective transactivation, DNA-binding and oligomerization domains. Both p73 and p63 transactivate p53-regulated promoters and induce apoptosis. Evidence suggests that both p73 and p63 may mediate apoptosis via some of the same mechanisms that are utilized by p53. However, both p73 and p63 exhibit features that are different from those of p53. Hence, both p73 and p63 are predicted to mediate apoptosis via mechanisms that are completely distinct from those engaged by p53. J. Cell. Physiol. 182:171-181, 2000. Published 2000 Wiley-Liss, Inc.

RASSF1A (RAS-association domain family 1, isoform A) is a newer tumor suppressor that binds to and stabilizes microtubules as well as induces M-phase cell cycle arrest. Several other proteins that interact with and stabilize microtubules also undergo mitotic phase phosphorylation to regulate microtubule dynamics and M-phase cell cycle progression. Currently, however, there is a paucity of information regarding the phosphorylation status of RASS-F1A and its regulation during mitosis. In this study, for the first time, we demonstrate that Aurora-A is a RASSF1A kinase and, to the best of our knowledge, this is also the first study reporting the identification of a kinase for RASSF1A. We show that the mitotic kinase Aurora-A directly interacts with and phosphorylates RASSF1 and that RASSF1A is phosphorylated by Aurora-A during mitosis. These findings therefore link an important oncogenic mitotic kinase to regulate RASSF1A tumor suppressor. Aurora-A appears to phosphorylate RASSF1A at Threonine202 and/or Serine203 that reside within the known microtubule-binding domain of RASSF1A. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of RASSF1A, disrupt RASSF1A interactions with microtubules and abolish its ability to induce M-phase cell cycle arrest. Our results further demonstrate that Aurora-A overexpression also interferes with RASSF1A-mediated growth suppression. In view of our results, we propose that Aurora-A-mediated phosphorylation of RASSF1A is a novel mechanism that regulates the ability of this tumor suppressor to interact with microtubules and modulate M-phase cell cycle progression.