title: Spinophilin acts as a tumor suppressor by regulating Rb phosphorylation.
abstract: The scaffold protein Spinophilin (SPN) is a regulatory subunit of phosphatase1a located at 17q21.33. This region is frequently associated with microsatellite instability and LOH containing a relatively high density of known tumor suppressor genes, including BRCA1. Several linkage studies have suggested the existence of an unknown tumor suppressor gene distal to BRCA1. Spn may be this gene, but the mechanism through which this gene makes its contribution to cancer has not been described. In this study, we aimed to determine how loss of Spn may contribute to tumorigenesis. We explored the contribution of SPN to PP1a-mediated Rb regulation. We found that the loss of Spn downregulated PPP1CA and PP1a activity, resulting in a high level of phosphorylated Rb and increased ARF and p53 activity. However, in the absence of p53, reduced levels of SPN enhanced the tumorigenic potential of the cells. Furthermore, the ectopic expression of SPN in human tumor cells greatly reduced cell growth. Taken together, our results demonstrate that the loss of Spn induces a proliferative response by increasing Rb phosphorylation, which, in turn, activates p53, thereby neutralizing the proliferative response. We suggest that Spn may be the tumor suppressor gene located at 17q21.33 acting through Rb regulation.
authors.affiliation: Experimental Therapeutics Programme, Instituto de Biomedicina de Sevilla/HUVR, Sevilla, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Ferrer
authors.forename: Carmen
authors.initials: C
authors.lastname: Blanco-Aparicio
authors.forename: Sandra
authors.initials: S
authors.lastname: Peregrina
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Jesús
authors.initials: J
authors.lastname: Fominaya
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Cecilia
authors.forename: Matilde
authors.initials: M
authors.lastname: Lleonart
authors.forename: Javier
authors.initials: J
authors.lastname: Hernandez-Losa
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramon y Cajal
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099273:Neurabins
chemical_list: D020823:ADP-Ribosylation Factor 1; D004317:Doxorubicin; D005047:Etoposide; D006861:Hydrogen Peroxide; D008748:Methylcholanthrene; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D054645:Protein Phosphatase 1; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000099273:Neurabins; C527795:PPP1CA protein, mouse