Rb Protein Down-regulates the Stress-activated Signals through Inhibiting c-Jun N-terminal Kinase/Stress-activated Protein Kinase*

The Rb protein is the product of the retinoblastoma susceptibility gene and loss of Rb function is detected in many types of human cancers. Rb plays important roles in the regulation of cell proliferation, differentiation, senescence, and apoptotic cell death. Here we show that Rb can physically interact with c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK), thereby inhibiting intracellular signals mediated by JNK/SAPK. Both in vitro binding and in vitrokinase studies suggest that a carboxyl-terminal domain of Rb containing amino acids 768–928 might be crucial for inhibiting JNK/SAPK. In comparison, Rb did not affect enzymatic activity of either extracellular signal-regulated kinase 1 or p38. Ectopically expressed Rb also abrogated the apoptotic cell death induced by ultraviolet radiation or the activation of MEKK1, an upstream kinase that can stimulate the JNK/SAPK cascade. JNK/SAPK inhibition highlights a novel function of Rb, which may provide a new mechanism by which Rb regulates cell death. JNK/SAPK is a major protein kinase that can be stimulated in response to a variety of cellular stresses. Our results, therefore, suggest that Rb, by inhibiting JNK/SAPK, may act as a negative regulator in stress-activated intracellular signaling cascades.

[1]  Y. Ip,et al.  Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. , 1998, Current opinion in cell biology.

[2]  J. Wang,et al.  The caspase-RB connection in cell death. , 1998, Trends in cell biology.

[3]  L. Magnaghi-Jaulin,et al.  Retinoblastoma protein represses transcription by recruiting a histone deacetylase , 1998, Nature.

[4]  Tony Kouzarides,et al.  Retinoblastoma protein recruits histone deacetylase to repress transcription , 1998, Nature.

[5]  E. Choi,et al.  Nitric oxide modulates the c-Jun N-terminal kinase/stress-activated protein kinase activity through activating c-Jun N-terminal kinase kinase. , 1997, Biochemistry.

[6]  Y. Oh,et al.  Activation of c-Jun N-terminal Kinase Antagonizes an Anti-apoptotic Action of Bcl-2* , 1997, The Journal of Biological Chemistry.

[7]  Sibylle Mittnacht,et al.  Differential Phosphorylation of the Retinoblastoma Protein by G1/S Cyclin-dependent Kinases* , 1997, The Journal of Biological Chemistry.

[8]  Seamus J. Martin,et al.  Degradation of Retinoblastoma Protein in Tumor Necrosis Factor- and CD95-induced Cell Death* , 1997, The Journal of Biological Chemistry.

[9]  F. Kaye,et al.  Apoptosis is associated with cleavage of a 5 kDa fragment from RB which mimics dephosphorylation and modulates E2F binding , 1997, Oncogene.

[10]  R. Davis,et al.  The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. , 1996, The Journal of biological chemistry.

[11]  A. Porter,et al.  Specific cleavage of the retinoblastoma protein by an ICE‐like protease in apoptosis. , 1996, The EMBO journal.

[12]  E. Choi,et al.  A non-enzymatic p21 protein inhibitor of stress-activated protein kinases , 1996, Nature.

[13]  L. Zon,et al.  Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis , 1996, Nature.

[14]  L. Zon,et al.  Signal Transduction Pathways Regulated by Mitogen-activated/Extracellular Response Kinase Kinase Kinase Induce Cell Death (*) , 1996, The Journal of Biological Chemistry.

[15]  T. Kouzarides.  Functions of pRb and p53: what's the connection? , 1995, Trends in cell biology.

[16]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[17]  T. Hambuch,et al.  p53 dependent growth suppression by the c-Abl nuclear tyrosine kinase. , 1995, Oncogene.

[18]  W. Sellers,et al.  Interaction between the retinoblastoma protein and the oncoprotein MDM2 , 1995, Nature.

[19]  G. Wahl,et al.  Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[21]  M. Karin,et al.  Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. , 1995, Science.

[22]  Jiahuai Han,et al.  Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms , 1995, Science.

[23]  M. Israel,et al.  Inhibition of apoptosis by the retinoblastoma gene product. , 1995, The EMBO journal.

[24]  L. Zon,et al.  Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun , 1994, Nature.

[25]  J. Woodgett,et al.  The stress-activated protein kinase subfamily of c-Jun kinases , 1994, Nature.

[26]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

[27]  P. J. Welch,et al.  A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle , 1993, Cell.

[28]  R. Weinberg,et al.  Effects of an Rb mutation in the mouse , 1992, Nature.

[29]  A. Berns,et al.  Requirement for a functional Rb-1 gene in murine development , 1992, Nature.

[30]  A. Bradley,et al.  Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis , 1992, Nature.

[31]  W. Schaffner,et al.  Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. , 1989, Nucleic acids research.

[32]  Y Taya,et al.  RB kinases and RB-binding proteins: new points of view. , 1997, Trends in biochemical sciences.