The early onset breast cancer patients (age ≤ 40) often display higher incidence of axillary lymph node metastasis, and poorer five-year survival than the late-onset patients. To identify the genes and molecules associated with poor prognosis of early onset breast cancer, we examined gene expression profiles from paired breast normal/tumor tissues, and coupled with Gene Ontology and public data base analysis. Our data showed that the expression of GAS7b gene was lower in the early onset breast cancer patients as compared to the elder patients. We found that GAS7 was associated with CYFIP1 and WAVE2 complex to suppress breast cancer metastasis via blocking CYFIP1 and Rac1 protein interaction, actin polymerization, and β1-integrin/FAK/Src signaling. We further demonstrated that p53 directly regulated GAS7 gene expression, which was inversely correlated with p53 mutations in breast cancer specimens. Our study uncover a novel regulatory mechanism of p53 in early onset breast cancer progression through GAS7–CYFIP1-mediated signaling pathways.

The class 3 Semaphorins Sema3A and Sema3F are potent axonal repellents that cause repulsion by binding Neuropilin-1 and Neuropilin-2, respectively. Plexins are implicated as signaling coreceptors for the Neuropilins, but the identity of the Plexins that transduce Sema3A and Sema3F responses in vivo is uncertain. Here, we show that Plexin-A3 and -A4 are key determinants of these responses, through analysis of a Plexin-A3/Plexin-A4 double mutant mouse. Sensory and sympathetic neurons from the double mutant are insensitive to Sema3A and Sema3F in vitro, and defects in axonal projections in vivo correspond to those seen in Neuropilin-1 and -2 mutants. Interestingly, we found a differential requirement for these two Plexins: signaling via Neuropilin-1 is mediated principally by Plexin-A4, whereas signaling via Neuropilin-2 is mediated principally by Plexin-A3. Thus, Plexin-A3 and -A4 contribute to the specificity of axonal responses to class 3 Semaphorins.

Caveolin-1, a 21-to 24-kd protein, is the principal component of caveolae, which are special invaginated microdomains of the plasma membrane present in most mammalian cells. 1 It is well established that caveolin-1 is a tumor suppressor gene. Caveolin-1 mRNA and protein expression are frequently lost in human cancer cell lines. Re-expression of caveolin-1 in oncogenically transformed cell lines inhibits tumor cell growth and reduces tumorigenicity. [2][3][4][5][6] Several mechanisms have been proposed for caveolin-1 to function as a tumor suppressor. Caveolin-1 may exert its tumor-growth inhibition by contact inactivation of signaling molecules such as v-src, Ha-Ras, protein kinase A, PKC, and p42/44 MAP kinase within caveolae. [7][8][9][10] In addition, down-regulation of caveolin-1 in colon carcinoma cells has been shown to prevent the degradation of inducible nitric oxide synthase via the proteosome pathway, which, in turn, increases the local nitric oxide concentration to facilitate tumorigenesis. 11 Caveolin-1 can also function as a tumor metastasispromoting molecule, which is unrelated to its obvious function of cell growth inhibition. 12 Elevated expression of caveolin-1 is found to be associated with progression of prostate, colon, and breast carcinoma. 13,14 Inhibition of c-myc-induced apoptosis by caveolin-1 was recently proposed to promote progression of prostate cancer, 15 and it may serve as a prognostic indicator for these patients. 16 Nonetheless, it still remains unclear whether and how caveolin-1 can potentiate tumor progression in other types of human cancer.In the present study, we investigated the expression pattern of caveolin-1 both in a series of lung carcinoma cell lines (CLs) with varying invasive/metastatic ability 17

The key gluconeogenic enzyme, fructose1,6-bisphosphatase (FBPase), is induced when Saccharomyces cerevisiae are starved of glucose. FBPase is targeted from the cytosol to the yeast vacuole for degradation when glucose-starved cells are replenished with fresh glucose. Several vid mutants defective in the glucose-induced degradation of FBPase in the vacuole have been isolated. In some vid mutants, FBPase is found in punctate structures in the cytoplasm. When extracts from these cells are fractionated, a substantial amount of FBPase is sedimentable in the high speed pellet, suggesting that FBPase is associated with intracellular structures in these vid mutants. In this paper we investigated whether FBPase association with intracellular structures also existed in wild-type cells. We report the purification of novel FBPase-associated vesicles from wild-type cells to near homogeneity. Kinetic studies indicate that FBPase association with these vesicles is stimulated by glucose and occurs only transiently, suggesting that these vesicles are intermediate in the FBPase degradation pathway. Fractionation analysis demonstrates that these vesicles are distinct from known organelles such as the vacuole, ER, Golgi, mitochondria, peroxisomes, endosomes, COPI, or COPII vesicles. Under EM, these vesicles are 30–40 nm in diam. Proteinase K experiments indicate that the majority of FBPase is sequestered inside the vesicles. We propose that FBPase is imported into these vesicles before entering the vacuole.

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