Eppley Institute for Research in Cancer and Allied Diseases

About: Eppley Institute for Research in Cancer and Allied Diseases is a based out in . It is known for research contribution in the topics: Pancreatic cancer & Cancer. The organization has 965 authors who have published 1396 publications receiving 58994 citations.

BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis

Abstract: It has been widely accepted that mitochondria-dependent apoptosis initiates when select BH3-only proteins (BID, BIM, etc.) directly engage and allosterically activate effector proteins BAX/BAK. Here, through reconstitution of cells lacking all eight pro-apoptotic BH3-only proteins, we demonstrate that all BH3-only proteins primarily target the anti-apoptotic BCL-2 proteins BCL-xL/MCL-1, whose simultaneous suppression enables membrane-mediated spontaneous activation of BAX/BAK. BH3-only proteins’ apoptotic activities correlate with affinities for BCL-xL/MCL-1 instead of abilities to directly activate BAX/BAK. Further, BID and BIM do not distinguish BAX from BAK or accelerate BAX/BAK activation following inactivation of BCL-xL/MCL-1. Remarkably, death ligand-induced apoptosis in cells lacking BH3-only proteins and MCL-1 is fully restored by BID mutants capable of neutralizing BCL-xL, but not direct activation of BAX/BAK. Taken together, our findings provide a “Membrane-mediated Permissive” model, in which the BH3-only proteins only indirectly activate BAX/BAK by neutralizing the anti-apoptotic BCL-2 proteins, and thus allowing BAX/BAK to undergo unimpeded, spontaneous activation in the mitochondrial outer membrane milieu, leading to apoptosis initiation.

The Janus Kinase 2 Is Required for Expression and Nuclear Accumulation of Cyclin D1 in Proliferating Mammary Epithelial Cells

Abstract: Using a conditional knockout approach, we previously demonstrated that the Janus kinase 2 (Jak2) is crucial for prolactin (PRL) signaling and normal mammary gland development. PRL is suggested to synchronously activate multiple signaling cascades that emerge on the PRL receptor (PRLR). This study demonstrates that Jak2 is essential for the activation of the signal transducer and activator of transcription 5 (Stat5) and expression of Cish (cytokine-inducible SH2-containing protein), a Stat5-responsive negative regulator of Jak/Stat signaling. However, Jak2 is dispensable for the PRL-induced activation of c-Src, focal adhesion kinase, and the MAPK pathway. Despite activation of these kinases that are commonly associated with proliferative responses, the ablation of Jak2 reduces the multiplication of immortalized mammary epithelial cells (MECs). Our studies show that signaling through Jak2 controls not only the transcriptional activation of the Cyclin D1 gene, but, more importantly, it regulates the accumulation of the Cyclin D1 protein in the nucleus by altering the activity of signal transducers that mediate the phosphorylation and subsequent nuclear export of Cyclin D1. In particular, the levels of activated Akt (protein kinase B) and inactive glycogen synthase kinase-3beta (i.e. a kinase that regulates the nuclear export and degradation of Cyclin D1) are reduced in MECs lacking Jak2. The proliferation of Jak2-deficient MECs can be rescued by expressing of a mutant form of Cyclin D1 that cannot be phosphorylated by glycogen synthase kinase-3beta and therefore constitutively resides in the nucleus. Besides discriminating Jak2-dependent and Jak2-independent signaling events emerging from the PRLR, our observations provide a possible mechanism for phenotypic similarities between Cyclin D1 knockouts and females lacking individual members of the PRLR signaling cascade, in particular the PRLR, Jak2, and Stat5.