Adhesion Molecules-28

Advances and Experimental-4

Aging-9

Agricultural Biotechnology-37

Angiogenesis-29

Antisense-4

Apoptosis-49

Atherosclerosis-12

Autoimmunity-69

Bacterial Virulence-18

Bioinformatics-13

BioMaterials-18

Biosurfactants-1

Biotechnology-102

Cancer Genetics-25

Cancer Metastasis-19

Cell Biology-16

Cell Cycle-34

Cell Metabolism-327

Channels and Transporters-79

Chaperones-11

Circadian Rhythms-13

Coagulation-14

Cytokines/Growth Factors-52

Development-223

DNA-56

DNA Surveillance and Repair-42

Drug Design-17

Endocrine-66

Evolution-33

Extracellular Matrix-30

Gastroenterology-52

Gene Expression-178

Gene Therapy-53

Heart-61

Heat Shock Proteins-19

Hematology-11

Immunology-93

Infectious Disease-71

Ischemia-Reperfusion-33

Leptin and Leptin Antagonists-1

Medical-26

MHC-17

Mitochondria-17

Molecular Biology-45

Molecular Complexes and Signaling-1

Nanomedicine-30

Neurodegenerative Disease-72

Neuropharmacology-112

Neuroscience-38

Nucleus-15

Oncogenes-8

Oncology-87

Parasitic Disease-12

Pharmacogenomics-14

Prebiotic Evolution-6

Protein-12

Reproductive Biology-60

RNA-152

Signal Transduction-186

Stem Cells-80

Surgery-37

T-Cell Activation-12

Tissue Engineering-116

Transplant-51

Vaccines-82

Viruses-85

Chapter category: Gene Therapy

Regulation of Rb Function by Noncyclin Dependent Kinases

Chapter authors:
Jaya Padmanabhan and Srikumar P. Chellappan

Inactivation of the retinoblastoma tumor suppressor protein, Rb, is necessary for the normal progression of the mammalian cell cycle.1 Studies over the past fifteen years have shown that Rb protein is inactivated by kinases associated with cyclins, especially cyclins D and E, which facilitate the entry of cells from the G1 to S phase.1-3 Though the cyclin/cdk mediated inactivation of Rb has been well studied, the role of other kinases in regulating Rb function is relatively less understood.4 It has been shown that components of the MAP kinase cascade, including ERK kinases as well as the Raf-1 kinase can phosphorylate Rb efficiently in response to proliferative signals.5,6 A physiological role for Raf-1 in inactivating Rb during cell cycle progression has been established.7 These kinases seem to work in conjunction with the cyclin-cdks, facilitating phosphorylation by the latter; at the same time, over-expression of Raf-1 could inactivate Rb as efficiently as cyclin-cdks.6,7 Similarly, it has been shown that Rb is inactivated upon apoptotic signaling as well.8-10 Such inactivation events appear to be mediated by the p38 kinase in a human T-cell leukemia system as well as a neuronal system.11,12 The inactivation of Rb upon apoptotic signaling seems to be totally independent of cyclins and cdks and occurring on different sites on the Rb protein.13 In addition to the p38 kinase, the stress-induced kinase JNK1 has been shown to affect Rb and E2F functions in certain apoptotic situations.11,14 Recently, the apoptosis signal regulating kinase, ASK1, was found to interact with Rb and overcome its anti-apoptotic activities.15 These studies suggest that while cyclin dependent kinases are the predominant regulators of Rb, especially during cell cycle progression, other kinases are capable of functionally inactivating Rb in response to multiple stimuli. Since inactivation of the Rb protein is widespread in a wide array of human tumors,10,16,17 understanding the mechanisms that inactivate Rb in response to normal physiological stimuli would be valuable in developing novel therapeutic strategies to combat cancer.

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