title: Cell cycle restriction is more important than apoptosis induction for RASSF1A protein tumor suppression.
abstract: The Ras association domain family protein 1A (RASSF1A) is arguably one of the most frequently inactivated tumor suppressors in human cancer. RASSF1A modulates apoptosis via the Hippo and Bax pathways but also modulates the cell cycle. In part, cell cycle regulation appears to be dependent upon the ability of RASSF1A to complex with microtubules and regulate their dynamics. Which property of RASSF1A, apoptosis induction or microtubule regulation, is responsible for its tumor suppressor function is not known. We have identified a short conserved motif that is essential for the binding of RASSF family proteins with microtubule-associated proteins. By making a single point mutation in the motif, we were able to generate a RASSF1A variant that retains wild-type apoptotic properties but completely loses the ability to bind microtubule-associated proteins and complex with microtubules. Comparison of this mutant to wild-type RASSF1A showed that, despite retaining its proapoptotic properties, the mutant was completely unable to induce cell cycle arrest or suppress the tumorigenic phenotype. Therefore, it appears that the cell cycle/microtubule effects of RASSF1A are key to its tumor suppressor function rather than its apoptotic effects.
authors.affiliation: From the Departments of Medicine.
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.affiliation: From the Departments of Medicine.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Clark
authors.affiliation: From the Departments of Medicine.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Monaghan
authors.affiliation: Biochemistry and Molecular Biology, and.
authors.forename: M Lee
authors.initials: ML
authors.lastname: Schmidt
authors.affiliation: the Cell and Cancer Biology Branch, NCI, National Institutes of Health, Rockville, Maryland 20850.
authors.forename: Michele
authors.initials: M
authors.lastname: Vos
authors.affiliation: Pharmacology and Toxicology, James Graham Brown Cancer Center, Molecular Targets Program, University of Louisville, Louisville, Kentucky 40202 and gjclar01@louisville.edu.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Clark
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D018631:ras Proteins
keywords: Apoptosis; Cell Cycle; Microtubule-associated Protein (MAP); Oncogene; Ras; Ras Protein; Tumor Suppressor