A tumor-suppressing function in the epithelial adhesion protein Trask.

Trask/CDCP1 is a transmembrane glycoprotein widely expressed in epithelial tissues whose functions are just beginning to be understood, but include a role as an anti-adhesive effector of Src kinases. Early studies looking at RNA transcript levels seemed to suggest overexpression in some cancers, but immunostaining studies are now providing more accurate analyses of its expression. In an immuno-histochemical survey of human cancer specimens, we find that Trask expression is retained, reduced or sometimes lost in some tumors compared with their normal epithelial tissue counterparts. A survey of human cancer cell lines also show a similar wide variation in the expression of Trask, including some cell types with the loss of Trask expression, and additional cell types that have lost the physiological detachment-induced phosphorylation of Trask. Three experimental models were established to interrogate the role of Trask in tumor progression, including two gain-of-function models with tet-inducible expression of Trask in tumor cells lacking Trask expression, and one loss-of-function model to suppress Trask expression in tumor cells with abundant Trask expression. The induction of Trask expression and phosphorylation in MCF-7 cells and in 3T3v-src cells was associated with a reduction in tumor metastases while the shRNA-induced knockdown of Trask in L3.6pl cancer cells was associated with increased tumor metastases. The results from these three models are consistent with a tumor-suppressing role for Trask. These data identify Trask as one of several potential candidates for functionally relevant tumor suppressors on the 3p21.3 region of the genome frequently lost in human cancers.

Cloning and characterization of Hepp, a novel gene expressed preferentially in hematopoietic progenitors and mature blood cells.

Through differential screening of mouse hematopoietic stem cell (HSC) and progenitor-subtracted cDNA libraries we have identified a progenitor cell-specific transcript that represents a novel gene, named Hepp (hematopoietic progenitor protein). The mouse Hepp gene encodes a protein of 237 amino acids with no detectable known functional domains or motifs. Lack of invertebrate orthologs and a high degree of evolutionary conservation of the peptide sequence in vertebrate species (zebrafish, mouse, human) suggest that the Hepp gene could have conserved although as yet unknown function in vertebrates. Mouse Hepp shows a restricted expression pattern in adult tissues and is transcribed at a very low level in heart, lung, spleen, and thymus and at a higher level in muscle. During embryonic hematopoiesis Hepp is not expressed in mouse fetal liver HSC (Sca-1(+)c-kit(+)AA4.1(+)Lin(-) cells), but is abundantly transcribed in the population of hematopoietic progenitors (AA4.1(-) cells). Similarly, during adult hematopoiesis Hepp is not transcribed in the highly enriched population of bone marrow HSC (Rh-123(low)Sca-1(+)c-kit(+)Lin(-) cells), but its expression is upregulated as a greater heterogeneous population of bone marrow HSC (Lin(-)Sca-1(+) cells) differentiates into progenitors (Lin(-)Sca-1(-) cells) and more mature lymphoid and myeloid cell types. A restricted pattern of expression in adult tissues and preferential expression in both fetal and adult hematopoietic progenitors and mature blood cells suggest that Hepp could be involved in molecular regulation of HSC and progenitor cell lineage commitment and differentiation.