In recent years, members of the protein kinase family have been discovered at an accelerated pace. Most were first described, not through the traditional biochemical approach of protein purification and enzyme assay, but as putative protein kinase amino acid sequences deduced from the nucleotide sequences of molecularly cloned genes or complementary DNAs. Phylogenetic mapping of the conserved protein kinase catalytic domains can serve as a useful first step in the functional characterization of these newly identified family members.

http://science.sciencemag.org/content/sci/241/4861/42.full.pdf

The protein kinase family: conserved features and deduced phylogeny of the catalytic domains.

The small (40S) subunit of eukaryotic ribosomes is believed to bind initially at the capped 5'-end of messenger RNA and then migrate, stopping at the first AUG codon in a favorable context for initiating translation. The first-AUG rule is not absolute, but there are rules for breaking the rule. Some anomalous observations that seemed to contradict the scanning mechanism now appear to be artifacts. A few genuine anomalies remain unexplained.

/pdf/the-scanning-model-for-translation-an-update-52r2in8l71.pdf

The scanning model for translation: an update.

The complementary DNAs and genes encoding the four major human myeloid growth factors--granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3--have all been molecularly cloned. These DNA clones have proved valuable for studying the molecular biology of these important regulatory molecules as well as for the large-scale production of the recombinant growth factor proteins. These advances have led to a much better understanding of the role of the myeloid growth factors in regulating hematopoiesis in vivo that should soon find practical application in clinical medicine.

https://science.sciencemag.org/content/sci/236/4806/1229.full.pdf

The human hematopoietic colony-stimulating factors

Five structural features in mRNAs have been found to contribute to the fidelity and efficiency of initiation by eukaryotic ribosomes. Scrutiny of vertebrate cDNA sequences in light of these criteria reveals a set of transcripts--encoding oncoproteins, growth factors, transcription factors, and other regulatory proteins--that seem designed to be translated poorly. Thus, throttling at the level of translation may be a critical component of gene regulation in vertebrates. An alternative interpretation is that some (perhaps many) cDNAs with encumbered 5' noncoding sequences represent mRNA precursors, which would imply extensive regulation at a posttranscriptional step that precedes translation.

https://rupress.org/jcb/article-pdf/115/4/887/1062268/887.pdf

An analysis of vertebrate mRNA sequences: intimations of translational control.

Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia

We have isolated cDNAs representing a previously unrecognized human gene that apparently encodes a protein-tyrosine kinase. We have designated the gene as HCK (hemopoietic cell kinase) because its expression is prominent in the lymphoid and myeloid lineages of hemopoiesis. Expression in granulocytic and monocytic leukemia cells increases after the cells have been induced to differentiate. The 57-kilodalton protein encoded by HCK resembles the product of the proto-oncogene c-src and is therefore likely to be a peripheral membrane protein. HCK is located on human chromosome 20 at bands q11-12, a region that is affected by interstitial deletions in some acute myeloid leukemias and myeloproliferative disorders. Our findings add to the diversity of protein-tyrosine kinases that may serve specialized functions in hemopoietic cells, and they raise the possibility that damage to HCK may contribute to the pathogenesis of some human leukemias.

Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells.

The CSF-1 gene encodes a hematopoietic colony-stimulating factor (CSF) that promotes growth, differentiation, and survival of mononuclear phagocytes. By using somatic cell hybrids and in situ hybridization, we localized this gene to human chromosome 5 at bands q31 to q35, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the CSF-1 gene was found to be deleted in the 5q- chromosome of a patient with refractory anemia who had a del(5)(q15q33.3) and in that of a second patient with acute nonlymphocytic leukemia de novo who had a similar distal breakpoint [del(5)(q13q33.3)]. The gene was present in the deleted chromosome of a third patient, with therapy-related acute nonlymphocytic leukemia, who had a more proximal breakpoint in band q33 [del(5)(q22q33.1)]. Hybridization of the CSF-1 probe to metaphase cells of a fourth patient, with acute nonlymphocytic leukemia de novo, who had a rearrangement of chromosomes 5 and 21 [ins(21;5)(q22;q31.3q33.1)] resulted in labeling of the breakpoint junctions of both rearranged chromosomes; this suggested that CSF-1 is located at 5q33.1. Thus, a small segment of chromosome 5 contains GM-CSF (the gene encoding the granulocyte-macrophage CSF), CSF-1, and FMS, which encodes the CSF-1 receptor, in that order from the centromere; this cluster of genes may be involved in the altered hematopoiesis associated with a deletion of 5q.

Assignment of CSF-1 to 5q33.1: evidence for clustering of genes regulating hematopoiesis and for their involvement in the deletion of the long arm of chromosome 5 in myeloid disorders

Assignment of the GM-CSF, CSF-1, and FMS Genes to Human Chromosome 5 Provides Evidence for Linkage of a Family of Genes Regulating Hematopoiesis and for Their Involvement in the Deletion (5q) in Myeloid Disorders

The G-CSF gene encodes a hematopoietic colony-stimulating factor (CSF) that promotes growth, differentiation, and survival of neutrophilic granulocytes. By analysis of somatic cell hybrids and in situ chromosomal hybridization, we localized this gene to human chromosome 17, at bands q11 to q12, the region of the breakpoint on chromosome 17 in the 15;17 translocation [t(15;17)] characteristic of acute promyelocytic leukemia. To determine the position of the G-CSF gene in relation to the breakpoint junctions and to evaluate the possible role of G-CSF in the pathogenesis of promyelocytic leukemia, we applied the techniques of in situ chromosomal hybridization and Southern blot analysis to leukemia cells from eight acute promyelocytic leukemia patients who had a t(15;17). Our results indicate that the G-CSF gene is proximal to the breakpoint of the t(15;17) and that this gene remains on the rearranged chromosome 17. Southern blot analysis using conventional and pulsed-field gel electrophoresis did not reveal rearranged restriction fragments, indicating that no rearrangements had occurred within the G-CSF gene or in surrounding sequences.

Mark J. Pettenati

Papers

Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells.

Assignment of CSF-1 to 5q33.1: evidence for clustering of genes regulating hematopoiesis and for their involvement in the deletion of the long arm of chromosome 5 in myeloid disorders

Assignment of the GM-CSF, CSF-1, and FMS Genes to Human Chromosome 5 Provides Evidence for Linkage of a Family of Genes Regulating Hematopoiesis and for Their Involvement in the Deletion (5q) in Myeloid Disorders

Chromosomal localization of the human G-CSF gene to 17q11 proximal to the breakpoint of the t(15;17) in acute promyelocytic leukemia.

Core binding factor acute myeloid leukemia. Cancer and Leukemia Group B (CALGB) Study 8461.