Aberrant p27kip1 expression in endocrine and other tumors.

The p27kip1 (p27) gene encodes an inhibitor of cyclin-dependent kinase activity. The expression of p27 protein in normal and neoplastic tissues was investigated by immunoblotting and immunohistochemistry. Immunoblotting studies detected a 27-kd protein band that was decreased in neoplastic pituitary tissues compared with normal pituitary. Immunostaining of 177 tissues showed abundant expression of p27 protein in normal tissues with decreased numbers of immunoreactive cells in adenomas and carcinomas in both endocrine and nonendocrine tissues. p27 expression was inversely related to the proliferation marker Ki-67 antigen detected with monoclonal antibody MIB-1. Parathyroid adenomas and hyperplasias had similar Ki-67 labeling indices; however, hyperplasias had threefold more p27-positive cells than parathyroid adenomas, suggesting that p27 immunostaining may be useful in distinguishing between these two conditions. These results indicate that there is widespread aberrant p27 expression in hyperplastic tissues and in benign and malignant neoplasms compared with normal tissues. Immunohistochemical analysis of p27 along with Ki-67 may be used to assess the biological behavior of various neoplasms, to classify hyperplastic and neoplastic tissues, and to study cell cycle regulation during tumor progression.

[1]  C. Bartram,et al.  Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies. , 1995, Cancer research.

[2]  R. Lloyd,et al.  Prolactin and Growth Hormone Synthesis and Thymidine Incorporation in Dissociated Rat Pituitary Tumor Cells , 1986, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[3]  L. Hengst,et al.  Translational Control of p27Kip1 Accumulation During the Cell Cycle , 1996, Science.

[4]  J. Geradts,et al.  High frequency of aberrant p16(INK4A) expression in human breast cancer. , 1996, The American journal of pathology.

[5]  M. Shuford,et al.  Tumor suppression and inhibition of aneuploid cell accumulation in human brain tumor cells by ectopic overexpression of the cyclin-dependent kinase inhibitor p27KIP1. , 1996, The Journal of clinical investigation.

[6]  Tony Hunter,et al.  p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21 , 1994, Cell.

[7]  K. Gatter,et al.  Monoclonal antibody Ki‐67: its use in histopathology , 1990, Histopathology.

[8]  C. O'keefe,et al.  Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. , 1994, Genes & development.

[9]  James M. Roberts,et al.  Assignment of the human p27Kip1 gene to 12p13 and its analysis in leukemias. , 1995, Cancer research.

[10]  James M. Roberts,et al.  p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. , 1994, Genes & development.

[11]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[12]  F. Haluska,et al.  Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. , 1995, Cancer research.

[13]  J. Massagué,et al.  Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. , 1995, Genes & development.

[14]  A. Kamb,et al.  Cell-cycle regulators and cancer. , 1995, Trends in genetics : TIG.

[15]  J. Roth,et al.  Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector. , 1995, Cancer research.

[16]  K. Post,et al.  Frequent loss of the P16INK4a gene product in human pituitary tumors. , 1996, Cancer research.

[17]  L. Jin,et al.  Transforming growth factor-beta and p27 expression in pituitary cells. , 1996, Endocrinology.

[18]  C. Sherr G1 phase progression: Cycling on cue , 1994, Cell.

[19]  R. van Driel,et al.  Ki-67 detects a nuclear matrix-associated proliferation-related antigen. II. Localization in mitotic cells and association with chromosomes. , 1989, Journal of cell science.

[20]  S. Elledge,et al.  p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. , 1995, Genes & development.

[21]  T. Hunter,et al.  Redistribution of the CDK inhibitor p27 between different cyclin.CDK complexes in the mouse fibroblast cell cycle and in cells arrested with lovastatin or ultraviolet irradiation. , 1995, Molecular biology of the cell.

[22]  Nobuyuki Shishido,et al.  Mice Lacking p27 Kip1 Display Increased Body Size, Multiple Organ Hyperplasia, Retinal Dysplasia, and Pituitary Tumors , 1996, Cell.

[23]  H. Koeffler,et al.  p27/Kip1 mutation found in breast cancer. , 1996, Cancer research.

[24]  H. Koeffler,et al.  Role of the cyclin-dependent kinase inhibitors in the development of cancer. , 1995, Blood.

[25]  J. Massagué,et al.  p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors. , 1995, Cancer research.

[26]  James M. Roberts,et al.  Requirement of p27Kip1 for Restriction Point Control of the Fibroblast Cell Cycle , 1996, Science.

[27]  James M. Roberts,et al.  A Syndrome of Multiorgan Hyperplasia with Features of Gigantism, Tumorigenesis, and Female Sterility in p27 Kip1 -Deficient Mice , 1996, Cell.

[28]  T. Hunter,et al.  Cyclins and cancer II: Cyclin D and CDK inhibitors come of age , 1994, Cell.

[29]  K. Manova-Todorova,et al.  Enhanced Growth of Mice Lacking the Cyclin-Dependent Kinase Inhibitor Function of p27 Kip1 , 1996, Cell.

[30]  James M. Roberts,et al.  Cloning of p27 Kip1 , a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals , 1994, Cell.

[31]  M. Roussel,et al.  Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6 , 1995, Molecular and cellular biology.

[32]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[33]  L. Tsai,et al.  The brain-specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[34]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[35]  M. J. Ravitz,et al.  Transforming growth factor beta-induced activation of cyclin E-cdk2 kinase and down-regulation of p27Kip1 in C3H 10T1/2 mouse fibroblasts. , 1995, Cancer research.

[36]  H Stein,et al.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. , 1984, Journal of immunology.

[37]  J. Gerdes,et al.  Immunohistological detection of tumour growth fraction (Ki-67 antigen) in formalin-fixed and routinely processed tissues. , 1992, The Journal of pathology.