K-Ras is essential for normal fetal liver erythropoiesis.

In vitro studies suggest that Ras activation is necessary for erythroid cell development. However, genetic inactivation of the Ras isoforms H-Ras, N-Ras, and K-Ras in mice reportedly did not affect adult or fetal erythropoiesis, though K-Ras(-/-) embryos were anemic. Given these discrepancies, we performed a more detailed analysis of fetal erythropoiesis in K-Ras(-/-) embryos. Day-13.5 K-Ras(-/-) embryos were pale with a marked reduction of mature erythrocytes in their fetal livers. The frequency and number of both early (erythroid burst-forming unit [BFU-E]) and late erythroid progenitors (erythroid colony-forming unit [CFU-E]) were reduced in K-Ras(-/-) fetal livers compared with wild-type controls and displayed a delay in terminal erythroid cell maturation. Further, K-Ras(-/-) hematopoietic progenitors had reduced proliferation in response to erythropoietin and Kit ligand compared with control cells. Thus, these studies identify K-Ras as a unique Ras isoform that is essential for regulating fetal erythropoiesis in vivo.

[1]  M. Yoder,et al.  Functional p85α gene is required for normal murine fetal erythropoiesis , 2003 .

[2]  J. Hancock,et al.  Ras proteins: different signals from different locations , 2003, Nature Reviews Molecular Cell Biology.

[3]  J. Schrader,et al.  Ras and relatives--job sharing and networking keep an old family together. , 2002, Experimental hematology.

[4]  J. B. Sajous,et al.  Ras signalling on the endoplasmic reticulum and the Golgi , 2002, Nature Cell Biology.

[5]  J. Hancock,et al.  Compartmentalization of Ras proteins. , 2001, Journal of cell science.

[6]  D. Bar-Sagi.  A Ras by Any Other Name , 2001, Molecular and Cellular Biology.

[7]  M. Malumbres,et al.  Targeted Genomic Disruption of H-ras and N-ras, Individually or in Combination, Reveals the Dispensability of Both Loci for Mouse Growth and Development , 2001, Molecular and Cellular Biology.

[8]  M. Lübbert,et al.  The role of Ras and other low molecular weight guanine nucleotide (GTP)-binding proteins during hematopoietic cell differentiation , 2000, Cellular and Molecular Life Sciences CMLS.

[9]  Z. Zhao,et al.  Stem cell factor and erythropoietin inhibit apoptosis of human erythroid progenitor cells through different signalling pathways , 2000, British journal of haematology.

[10]  D. Dumont,et al.  Epo regulates erythroid proliferation and differentiation through distinct signaling pathways: implication for erythropoiesis and Friend virus-induced erythroleukemia , 2000, Oncogene.

[11]  Sun-Hee Kim,et al.  Role of Ras/ERK-dependent pathway in the erythroid differentiation of K562 cells , 1999, Experimental & Molecular Medicine.

[12]  A. Miyajima,et al.  Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells: functional analysis of signaling molecules by retrovirus-mediated expression. , 1999, Blood.

[13]  H. Broxmeyer,et al.  Involvement of H-ras in erythroid differentiation of TF1 and human umbilical cord blood CD34 cells. , 1998, Blood cells, molecules & diseases.

[14]  R. Kucherlapati,et al.  K-ras is an essential gene in the mouse with partial functional overlap with N-ras. , 1997, Genes & development.

[15]  Jun Miyoshi,et al.  K-Ras is essential for the development of the mouse embryo , 1997, Oncogene.

[16]  R. Kucherlapati,et al.  The murine N-ras gene is not essential for growth and development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[17]  E. Nishida,et al.  Activation of mitogen-activated protein kinase cascade through erythropoietin receptor. , 1994, Biochemical and biophysical research communications.

[18]  E. Lapetina,et al.  Erythropoietin induces p21ras activation and p120GAP tyrosine phosphorylation in human erythroleukemia cells. , 1992, The Journal of biological chemistry.

[19]  M. Ogawa,et al.  Enhancement of the proliferation of murine fetal liver erythroid progenitors by infection with Harvey sarcoma virus. , 1990, Leukemia.

[20]  C. Marshall,et al.  All ras proteins are polyisoprenylated but only some are palmitoylated , 1989, Cell.

[21]  M. Yoder,et al.  Functional p85alpha gene is required for normal murine fetal erythropoiesis. , 2003, Blood.

[22]  P. Rebulla,et al.  Cord blood cells , 2001 .

[23]  M. Dai,et al.  Enhancement of proliferation and differentiation of erythroid progenitors by co-transduction of erythropoietin receptor and H-ras cDNAs into single CD343+ cord blood cells , 2000, Bone Marrow Transplantation.

[24]  C. Martínez-A,et al.  Ras proteins: recent advances and new functions. , 1999, Blood.

[25]  S. Krantz,et al.  Synergistic activation of MAP kinase (ERK1/2) by erythropoietin and stem cell factor is essential for expanded erythropoiesis. , 1998, Blood.