Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis

In animals, cells are dependent on extracellular signals to prevent apoptosis. However, using growth factor-dependent cells from Bax/Bak-deficient mice, we demonstrate that apoptosis is not essential to limit cell autonomous survival. Following growth factor withdrawal, Bax-/-Bak-/- cells activate autophagy, undergo progressive atrophy, and ultimately succumb to death. These effects result from loss of the ability to take up sufficient nutrients to maintain cellular bioenergetics. Despite abundant extracellular nutrients, growth factor-deprived cells maintain ATP production from catabolism of intracellular substrates through autophagy. Autophagy is essential for maintaining cell survival following growth factor withdrawal and can sustain viability for several weeks. During this time, cells respond to growth factor readdition by rapid restoration of the ability to take up and metabolize glucose and by subsequent recovery of their original size and proliferative potential. Thus, growth factor signal transduction is required to direct the utilization of sufficient exogenous nutrients to maintain cell viability.

[1]  C. Thompson,et al.  Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression. , 2003, Developmental cell.

[2]  S. Baldwin,et al.  Apoptosis is regulated by the rate of glucose transport in an interleukin 3 dependent cell line , 1994, The Journal of experimental medicine.

[3]  Daniel J. Klionsky,et al.  Autophagy in Health and Disease: A Double-Edged Sword , 2004, Science.

[4]  M. V. Vander Heiden,et al.  In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. , 2000, Molecular cell.

[5]  D. Scheuner,et al.  Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J C Reed,et al.  Mitochondria and apoptosis. , 1998, Science.

[7]  R. Kessin,et al.  Macroautophagy Is Required for Multicellular Development of the Social Amoeba Dictyostelium discoideum * , 2003, The Journal of Biological Chemistry.

[8]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[9]  S. Lowe,et al.  Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. , 1998, Genes & development.

[10]  M. Schlumpberger,et al.  Isolation of autophagocytosis mutants of Saccharomyces cerevisiae , 1994, FEBS letters.

[11]  O. Roger Anderson,et al.  Dictyostelium Macroautophagy Mutants Vary in the Severity of Their Developmental Defects* , 2004, Journal of Biological Chemistry.

[12]  S. Tsuboi,et al.  Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction , 1992, The Journal of cell biology.

[13]  David R. Plas,et al.  Growth Factors Can Influence Cell Growth and Survival through Effects on Glucose Metabolism , 2001, Molecular and Cellular Biology.

[14]  W. Zong,et al.  Alkylating DNA damage stimulates a regulated form of necrotic cell death. , 2004, Genes & development.

[15]  S. Korsmeyer,et al.  Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death , 2001, Science.

[16]  I. Germano,et al.  Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells , 2004, Cell Death and Differentiation.

[17]  P. Codogno,et al.  Distinct Classes of Phosphatidylinositol 3′-Kinases Are Involved in Signaling Pathways That Control Macroautophagy in HT-29 Cells* , 2000, The Journal of Biological Chemistry.

[18]  S. Korsmeyer,et al.  The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. , 2000, Molecular cell.

[19]  I. Conlon,et al.  Size Control in Animal Development , 1999, Cell.

[20]  C. Lamb,et al.  Programmed Cell Death in Plants. , 1997, The Plant cell.

[21]  C. Thompson,et al.  Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. , 2002, Molecular biology of the cell.

[22]  S. Tsuboi,et al.  Ultrastructural analysis of the autophagic process in yeast: detection of autophagosomes and their characterization , 1994, The Journal of cell biology.

[23]  N. Mizushima,et al.  Autophagosome formation in mammalian cells. , 2002, Cell structure and function.

[24]  Y. Tomino,et al.  MAP‐LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  T. Hollister,et al.  A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. , 2001, Cancer research.

[26]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[27]  Huanming Yang,et al.  A Draft Sequence of the Rice Genome (Oryza sativa L. ssp. indica) , 2002, Science.

[28]  Ajjai Alva,et al.  Regulation of an ATG7-beclin 1 Program of Autophagic Cell Death by Caspase-8 , 2004, Science.

[29]  Takeshi Tokuhisa,et al.  The role of autophagy during the early neonatal starvation period , 2004, Nature.

[30]  S. Korsmeyer,et al.  BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. , 2001, Molecular cell.

[31]  Y Li,et al.  [Mitochondria and apoptosis]. , 2000, Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine].

[32]  E. White,et al.  Exploiting different ways to die. , 2004, Genes & development.

[33]  Y. Kondo,et al.  Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells , 2004, Cancer Research.

[34]  v-Rel prevents apoptosis in transformed lymphoid cells and blocks TNFα-induced cell death , 1997, Oncogene.

[35]  Arnold J. Levine,et al.  Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. V. Heiden,et al.  Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. , 1999, Molecular cell.

[37]  D. Shibata,et al.  Leaf Senescence and Starvation-Induced Chlorosis Are Accelerated by the Disruption of an Arabidopsis Autophagy Gene1 , 2002, Plant Physiology.

[38]  E. Scolnick,et al.  Growth of factor-dependent hemopoietic precursor cell lines , 1980, The Journal of experimental medicine.

[39]  T. Mak,et al.  Apaf1 Is Required for Mitochondrial Pathways of Apoptosis and Brain Development , 1998, Cell.

[40]  I. Germano,et al.  Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. , 2003, Cancer research.

[41]  R. Bligny,et al.  Ultrastructural and biochemical characterization of autophagy in higher plant cells subjected to carbon deprivation: control by the supply of mitochondria with respiratory substrates , 1996, The Journal of cell biology.

[42]  S. R. Datta,et al.  BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis , 2003, Nature.

[43]  P. Seglen,et al.  Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. , 2004, Developmental cell.

[44]  Y. Ohsumi,et al.  Isolation and characterization of autophagy‐defective mutants of Saccharomyces cerevisiae , 1993, FEBS letters.

[45]  D. Hall,et al.  Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans , 2003, Science.

[46]  E. Lam,et al.  Controlled cell death, plant survival and development , 2004, Nature Reviews Molecular Cell Biology.

[47]  Daniel J Klionsky,et al.  Development by self-digestion: molecular mechanisms and biological functions of autophagy. , 2004, Developmental cell.

[48]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[49]  T. P. Neufeld,et al.  Role and regulation of starvation-induced autophagy in the Drosophila fat body. , 2004, Developmental cell.