Raf-1 kinase inhibitor protein: structure, function, regulation of cell signaling, and pivotal role in apoptosis.
The acquisition of resistance to conventional therapies such as radiation and chemotherapeutic drugs remains the major obstacle in the successful treatment of cancer patients. Tumor cells acquire resistance to apoptotic stimuli and it has been demonstrated that conventional therapies exert their cytotoxic activities primarily by inducing apoptosis in the cells. Resistance to radiation and chemotherapeutic drugs has led to the development of immunotherapy and gene therapy approaches with the intent of overcoming resistance to drugs and radiation as well as enhancing the specificity to eliminate tumor cells. However, cytotoxic lymphocytes primarily kill by apoptosis and, therefore, drug-resistant tumor cells may also be cross-resistant to immunotherapy. To evade apoptosis, tumor cells have adopted various mechanisms that interfere with the apoptotic signaling pathways and promote constitutive activation of cellular proliferation and survival pathways. Thus, modifications of the antiapoptotic genes in cancer cells are warranted for the effectiveness of conventional therapies as well as novel immunotherapeutic approaches. Such modifications will avert the resistant phenotype of the tumor cells and will render them susceptible to apoptosis. Current studies, both in vitro and preclinically in vivo, have been aimed at the modification and regulation of expression of apoptosis-related gene products and their activities. A novel protein designated Raf-1 kinase inhibitor protein (RKIP) has been partially characterized. RKIP is a member of the phosphatidylethanolamine-binding protein family. RKIP has been shown to disrupt the Raf-1-MEK1/2 [mitogen-activated protein kinase-ERK (extracellular signal-regulated kinase) kinase-1/2]-ERK1/2 and NF-kappaB signaling pathways, via physical interaction with Raf-1-MEK1/2 and NF-kappaB-inducing kinase or transforming growth factor beta-activated kinase-1, respectively, thereby abrogating the survival and antiapoptotic properties of these signaling pathways. In addition, RKIP has been shown to act as a signal modifier that enhances receptor signaling by inhibiting G protein-coupled receptor kinase-2. By regulating cell signaling, growth, and survival through its expression and activity, RKIP is considered to play a pivotal role in cancer, regulating apoptosis induced by drugs or immune-mediated stimuli. Overexpression of RKIP sensitizes tumor cells to chemotherapeutic drug-induced apoptosis. Also, induction of RKIP by drugs or anti-receptor antibodies sensitizes cancer cells to drug-induced apoptosis. In this review, we discuss the discovery, structure, function, and significance of RKIP in cancer.
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA.
Golaun
G
Odabaei
Devasis
D
Chatterjee
Ali R
AR
Jazirehi
Lee
L
Goodglick
Kam
K
Yeung
Benjamin
B
Bonavida
D000595:Amino Acid Sequence; D000727:Androgen-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001483:Base Sequence; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D054769:G-Protein-Coupled Receptor Kinase 2; D054770:G-Protein-Coupled Receptor Kinase 3; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D049488:Phosphatidylethanolamine Binding Protein; D010714:Phosphatidylethanolamines / Q000378:metabolism; D060789:Prostatein; D011487:Protein Conformation; D051381:Rats; D060765:Secretoglobins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014598:Uteroglobin; D051552:beta-Adrenergic Receptor Kinases; D060788:Mammaglobin B
D000727:Androgen-Binding Protein; D000970:Antineoplastic Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D054770:G-Protein-Coupled Receptor Kinase 3; D016328:NF-kappa B; D009363:Neoplasm Proteins; D049488:Phosphatidylethanolamine Binding Protein; D010714:Phosphatidylethanolamines; D060789:Prostatein; D060765:Secretoglobins; D014598:Uteroglobin; D051552:beta-Adrenergic Receptor Kinases; C511482:PEBP1 protein, human; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C483858:phosphatidylethanolamine; C517848:GRK3 protein, human; C517850:GRK3 protein, mouse; C496569:Grk2 protein, rat; C517851:Grk3 protein, rat; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B