The dark side of Ras: regulation of apoptosis

Mutational activation of Ras promotes oncogenesis by disrupting a multitude of normal cellular processes. Perhaps, best characterized and understood are the mechanisms by which oncogenic Ras promotes deregulated cell cycle progression and uncontrolled cellular proliferation. However, it is now clear that oncogenic Ras can also deregulate processes that control apoptosis. In light of the diversity of downstream effector targets known to facilitate Ras function, it is perhaps not surprising that Ras regulation of cell survival is complex, involving the balance and interplay of multiple signaling networks. While our understanding of these events is still far from complete, and is complicated by cell type and signaling context differences, several important mechanisms have begun to emerge. We review the role and mechanism of specific effectors in regulating the antiapoptotic (Raf, phosphatidylinositol 3-kinase and Tiam1) and apoptotic (Nore1 and RASSF1) actions of oncogenic Ras, and discuss the possibility that the effector actions of p120RasGAP make a significant contribution to Ras regulation of apoptotic events.

[1]  C. Y. Wang,et al.  Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. , 1997, Science.

[2]  K. Moelling,et al.  Regulation of Raf by Akt Controls Growth and Differentiation in Vascular Smooth Muscle Cells* , 2001, The Journal of Biological Chemistry.

[3]  R. Kerbel,et al.  Activated ras Prevents Downregulation of Bcl-XL Triggered by Detachment from the Extracellular Matrix , 2000, The Journal of cell biology.

[4]  M. Benito,et al.  Activated Ha-ras Induces Apoptosis by Association with Phosphorylated Bcl-2 in a Mitogen-activated Protein Kinase-independent Manner* , 1999, The Journal of Biological Chemistry.

[5]  E. Mekada,et al.  Ras/MEK signaling suppresses Myc-dependent apoptosis in cells transformed by c-myc and activated ras , 2000, Oncogene.

[6]  K. Moelling,et al.  Phosphorylation and regulation of Raf by Akt (protein kinase B). , 1999, Science.

[7]  L. Chin,et al.  Essential role for oncogenic Ras in tumour maintenance , 1999, Nature.

[8]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[9]  M. Coffey,et al.  Reovirus therapy of tumors with activated Ras pathway. , 1998, Science.

[10]  Theresa M. Grana,et al.  Rit, a non-lipid-modified Ras-related protein, transforms NIH3T3 cells without activating the ERK, JNK, p38 MAPK or PI3K/Akt pathways , 2000, Oncogene.

[11]  T. Pawson,et al.  Vascular system defects and neuronal apoptosis in mice lacking Ras GTPase-activating protein , 1995, Nature.

[12]  C. Widmann,et al.  The RasGAP N-terminal Fragment Generated by Caspase Cleavage Protects Cells in a Ras/PI3K/Akt-dependent Manner That Does Not Rely on NFκB Activation* , 2002, The Journal of Biological Chemistry.

[13]  S. Coniglio,et al.  Rac1 Protects Epithelial Cells against Anoikis* , 2001, The Journal of Biological Chemistry.

[14]  B. Kaina,et al.  Ras-related GTPase RhoB forces alkylation-induced apoptotic cell death. , 2000, Biochemical and biophysical research communications.

[15]  S. Frisch,et al.  Disruption of epithelial cell-matrix interactions induces apoptosis , 1994, The Journal of cell biology.

[16]  C. Der,et al.  The Ras branch of small GTPases: Ras family members don't fall far from the tree. , 2000, Current opinion in cell biology.

[17]  R. Kerbel,et al.  Massive programmed cell death in intestinal epithelial cells induced by three-dimensional growth conditions: suppression by mutant c-H-ras oncogene expression , 1995, The Journal of cell biology.

[18]  John Calvin Reed,et al.  Bcl-2 Targets the Protein Kinase Raf-1 to Mitochondria , 1996, Cell.

[19]  B. Tocqué,et al.  Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells , 1999, Oncogene.

[20]  S. R. Datta,et al.  Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. , 1999, Science.

[21]  G. Rosen,et al.  Proteolytic cleavage of Ras GTPase-activating protein during apoptosis , 1998, Cell Death and Differentiation.

[22]  G. Mills,et al.  Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway , 1999, Oncogene.

[23]  J. Zweier,et al.  Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts , 1997, Science.

[24]  M. Montminy,et al.  CREB Is a Regulatory Target for the Protein Kinase Akt/PKB* , 1998, The Journal of Biological Chemistry.

[25]  G. Evan,et al.  Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB , 1997, Nature.

[26]  G. Barber,et al.  Oncolytic Activity of Vesicular Stomatitis Virus Is Effective against Tumors Exhibiting Aberrant p53, Ras, or Myc Function and Involves the Induction of Apoptosis , 2001, Journal of Virology.

[27]  G. Trentin,et al.  A Mouse Homologue of the Drosophila Tumor Suppressor l(2)tid Gene Defines a Novel Ras GTPase-activating Protein (RasGAP)-binding Protein* , 2001, The Journal of Biological Chemistry.

[28]  Qiang Yu,et al.  Bcl-2, via Its BH4 Domain, Blocks Apoptotic Signaling Mediated by Mitochondrial Ras* , 2003, The Journal of Biological Chemistry.

[29]  J. Avruch,et al.  The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1 , 2002, Oncogene.

[30]  J. Romashkova,et al.  NF-κB is a target of AKT in anti-apoptotic PDGF signalling , 1999, Nature.

[31]  S. Yokoyama,et al.  Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21Ras in IL-3-dependent hematopoietic cells , 1997, Oncogene.

[32]  R. Cerione,et al.  Cdc42 Is a Substrate for Caspases and Influences Fas-induced Apoptosis* , 2001, The Journal of Biological Chemistry.

[33]  J. Camonis,et al.  Identification of Aurora Kinases as RasGAP Src Homology 3 Domain-binding Proteins* , 2002, The Journal of Biological Chemistry.

[34]  S. Sebti,et al.  Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice* , 2000, The Journal of Biological Chemistry.

[35]  K. Dee,et al.  Raf-induced effects on the differentiation and apoptosis of skeletal myoblasts are determined by the level of Raf signaling: abrogation of apoptosis by Raf is downstream of caspase 3 activation , 2002, Oncogene.

[36]  T. Ohyama,et al.  MST, a Physiological Caspase Substrate, Highly Sensitizes Apoptosis Both Upstream and Downstream of Caspase Activation* , 2001, The Journal of Biological Chemistry.

[37]  F. Miller,et al.  Ras Regulates Sympathetic Neuron Survival by Suppressing the p53-Mediated Cell Death Pathway , 1999, The Journal of Neuroscience.

[38]  John G. Collard,et al.  Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours , 2002, Nature.

[39]  Xiao-Rong Zeng,et al.  Regulation of Bcl-xL: a little bit of this and a little bit of STAT , 2000, Current opinion in oncology.

[40]  J. Downward,et al.  Matrix detachment induces caspase-dependent cytochrome c release from mitochondria: inhibition by PKB/Akt but not Raf signalling , 2000, Oncogene.

[41]  A. Cox,et al.  A Distinct Class of Dominant Negative Ras Mutants , 2002, The Journal of Biological Chemistry.

[42]  H. Ruan,et al.  p90RSK Blocks Bad-mediated Cell Death via a Protein Kinase C-dependent Pathway* , 1999, The Journal of Biological Chemistry.

[43]  K. Tyler,et al.  Reovirus-Induced Apoptosis Is Mediated by TRAIL , 2000, Journal of Virology.

[44]  Qin He,et al.  TC21 mediates transformation and cell survival via activation of phosphatidylinositol 3-kinase/Akt and NF-κB signaling pathway , 2002, Oncogene.

[45]  C. Marshall,et al.  PI-3-kinase is an essential anti-apoptotic effector in the proliferative response of primary human epithelial cells to mutant RAS , 2000, Oncogene.

[46]  Y. Kaziro,et al.  Analysis of Ras-dependent signals that prevent caspase-3 activation and apoptosis induced by cytokine deprivation in hematopoietic cells. , 2000, Biochemical and biophysical research communications.

[47]  B. Kaina,et al.  Ras-related GTPase RhoB Represses NF-κB Signaling* , 2001, The Journal of Biological Chemistry.

[48]  J. Schrader,et al.  M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line. , 1999, Blood.

[49]  Jennifer Y. Zhang,et al.  NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia , 2003, Nature.

[50]  A. Bell,et al.  Ras Uses the Novel Tumor Suppressor RASSF1 as an Effector to Mediate Apoptosis* , 2000, The Journal of Biological Chemistry.

[51]  V. Rangnekar,et al.  Oncogenic Ras Sensitizes Cells to Apoptosis by Par-4* , 1999, The Journal of Biological Chemistry.

[52]  D. Danley,et al.  D4-GDI, a Substrate of CPP32, Is Proteolyzed during Fas-induced Apoptosis (*) , 1996, The Journal of Biological Chemistry.

[53]  John Calvin Reed,et al.  R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl- 2 suppressible mechanism , 1995, The Journal of cell biology.

[54]  A. Tolkovsky,et al.  The Ras/Phosphatidylinositol 3-Kinase and Ras/ERK Pathways Function as Independent Survival Modules Each of Which Inhibits a Distinct Apoptotic Signaling Pathway in Sympathetic Neurons* , 2000, The Journal of Biological Chemistry.

[55]  F. McCormick,et al.  Opposing Effects of Ras on p53 Transcriptional Activation of mdm2 and Induction of p19ARF , 2000, Cell.

[56]  K. Hahn,et al.  Antiapoptotic Cdc42 mutants are potent activators of cellular transformation. , 2002, Biochemistry.

[57]  G. Prendergast,et al.  RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[58]  C. Widmann,et al.  Caspase-dependent Cleavage of Signaling Proteins during Apoptosis , 1998, The Journal of Biological Chemistry.