title: Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies.
abstract: It is now evident that the cell cycle machinery has a variety of elements negatively regulating cell cycle progression. However, among these negative regulators in cell cycle control, only 4 have been shown to be consistently involved in the development of human cancers as tumor suppressors: Rb (Retinoblastoma susceptibility protein), p53, and two recently identified cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are functional interrelations among these negative regulators in the cell cycle machinery, it is particularly interesting to investigate the multiplicity of inactivations of these tumor suppressors in human cancers, including leukemias/lymphomas. To address this point, we examined inactivations of these four genes in primary lymphoid malignancies by Southern blot and polymerase chain reaction-single-strand conformation polymorphism analyses. We also analyzed Rb protein expression by Western blot analysis. The p16INK4A and p15INK4B genes were homozygously deleted in 45 and 42 of 230 lymphoid tumor specimens, respectively. Inactivations of the Rb and p53 genes were 27 of 91 and 9 of 173 specimens, respectively. Forty-one (45.1%) of 91 samples examined for inactivations of all four tumor suppressors had one or more abnormalities of these four tumor-suppressor genes, indicating that dysregulation of cell cycle control is important for tumor development. Statistical analysis of interrelations among impairments of these four genes indicated that inactivations of the individual tumor-suppressor genes might occur almost independently. In some patients, disruptions of multiple tumor-suppressor genes occurred; 4 cases with p16INK4A, p15INK4B, and Rb inactivations; 2 cases with p16INK4A, p15INK4B, and p53 inactivations; and 1 case with Rb and p53 inactivations. It is suggested that disruptions of multiple tumor suppressors in a tumor cell confer an additional growth advantage on the tumor.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Hangaishi
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: N
authors.initials: N
authors.lastname: Imamura
authors.forename: S
authors.initials: S
authors.lastname: Miyawaki
authors.forename: Y
authors.initials: Y
authors.lastname: Miura
authors.forename: N
authors.initials: N
authors.lastname: Uike
authors.forename: C
authors.initials: C
authors.lastname: Shimazaki
authors.forename: N
authors.initials: N
authors.lastname: Emi
authors.forename: K
authors.initials: K
authors.lastname: Takeyama
authors.forename: S
authors.initials: S
authors.lastname: Hirosawa
authors.forename: N
authors.initials: N
authors.lastname: Kamada
authors.forename: Y
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Takemoto
authors.forename: T
authors.initials: T
authors.lastname: Kitani
authors.forename: K
authors.initials: K
authors.lastname: Toyama
authors.forename: S
authors.initials: S
authors.lastname: Ohtake
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: R
authors.initials: R
authors.lastname: Ueda
authors.forename: H
authors.initials: H
authors.lastname: Hirai
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D002675:Child, Preschool; D002869:Chromosome Aberrations; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D016193:G1 Phase / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D007231:Infant, Newborn; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins
chemical_list: C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins