AMBRA1, a Novel BH3-Like Protein: New Insights Into the AMBRA1-BCL2-Family Proteins Relationship.

Cellular homeostasis swings like a pendulum backward and forward between life and death. Two of the main processes, which regulate this equilibrium, are autophagy and apoptosis. While autophagy is a highly conserved self-digestion mechanism that mediates degradation of damaged or surplus components, apoptosis is a programmed cell suicide in which typical death signals induce the elimination of undesired cells. Both these processes are highly regulated by complex molecular machineries, including some common proteins whose "dual role" favors one process or the other. Among these proteins, the well-known antiapoptotic factor BCL2 downregulates autophagy through interactions with the essential autophagic effectors, BECN1/BECLIN 1 and AMBRA1. Recently, we have demonstrated that the proautophagic protein AMBRA1 contains a BH3 domain necessary for AMBRA1 binding with the antiapoptotic factor BCL2. We found that the AMBRA1-BCL2 couple have a "dual role" in autophagy and apoptosis: the mitochondrial pool of BCL2 is able to inhibit AMBRA1-dependent autophagy, whereas in cell death conditions, the cleaved form of AMBRA1 (AMBRA1CT), resulting from CASP/CASPASES-cleavage, abrogates the prosurvival activity of BCL2 and promotes a proapoptotic amplification loop. The CASP-cleaved form of AMBRA1 bound other antiapoptotic members of the BCL2 family proteins such as MCL1 and BCL2L1/BCL-X; by contrast, no binding could be detected with the proapoptotic-BCL2 factors such as BAK1/BAK and BAX. These findings underline an intricate interplay between autophagy and cell death in which the proautophagic protein AMBRA1 and the antiapoptotic BCL2 family members are the major players. Here, we give an overview of the AMBRA1-BCL2 family proteins interactome and its involvement in controlling life and cell death. We discuss a putative therapeutic target which offers the novel BH3 motif identified in the C-terminal part of AMBRA1.

Evaluation of the anterior pituitary function in the acute phase after spontaneous subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a potential cause of hypopituitarism. Most of the studies regarding the relationship between SAH and anterior pituitary function were retrospective and hormonal assessment was performed several months after SAH. AIM: To prospectively evaluate the prevalence of anterior pituitary hormone deficiencies in the acute phase after spontaneous SAH and their possible correlation with clinical and radiological parameters. METHODS: Pituitary function was tested in 60 patients within 72 h after spontaneous SAH. RESULTS: 56.9% of the patients showed at least one anterior pituitary hormone deficiency: gonadotropin and GH secretion failure represented the most prevalent hormonal deficiencies (33.3 and 22.0%, respectively), whereas ACTH and TSH deficiency was less frequent (7.1 and 1.8%, respectively). With the exception of secondary hypogonadism, the prevalence of other pituitary hormone deficiencies is in agreement with previous studies, which evaluated pituitary function on longterm follow up after SAH. No correlation was found between hypopituitarism and clinical status, as assessed with Hunt-Hess and Glascow Coma Scales. Moreover, no correlation was found between hypopituitarism and bleeding severity evaluated with Fisher's scale. CONCLUSIONS: We demonstrated a high prevalence of anterior pituitary hormone deficiencies acutely after SAH. Although part of GH and gonadotropin deficiencies might be a consequence of functional alteration due to SAH itself, the finding of low cortisol levels in this stressful condition strongly suggests the presence of true hypocortisolism. Therefore, an evaluation of pituitary function shortly after SAH might be useful to identify a subset of patients who deserve a more accurate follow-up.