Location, location, location: the role of cyclin D1 nuclear localization in cancer.
The control of cell proliferation is crucial in maintaining cellular homeostasis and loss of this mechanism is a principle hallmark of cancer cells. A primary target of growth factor signaling is the cyclin D1-dependent kinase (D1-CDK4/6) whose activity promotes G1 phase progression by phosphorylating the retinoblastoma protein (Rb) along with related pocket proteins 107 and p130, relieving inhibition of E2F family transcription factors. Cyclin D1 accumulation is regulated at multiple levels including transcription, post-translational activation and cellular localization throughout the cell cycle. While overexpression of cyclin D1 has been observed in a number of human cancers, mouse cancer models overexpressing D1 have fallen short of establishing a role for cyclin D1 in the initiation of malignant phenotypes suggesting an additional regulatory mechanism exists that prevents cyclin D1-driven cancer. This article will present an overview of current data investigating the regulation of cyclin D1 nuclear localization and the prevalence of these aberrations in cancer. Finally, future avenues of research involving cyclin D1 cellular localization and its regulation in cancer will be addressed.
Gladden
Andrew B
AB
Department of Cancer Biology, The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Diehl
J Alan
JA
D021581:Active Transport, Cell Nucleus; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D019927:Cyclin E / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C493841:BCAR1 protein, human; D018797:Cell Cycle Proteins; D050719:Crk-Associated Substrate Protein; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D019938:Cyclin D1; D044767:Ubiquitin-Protein Ligases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6