Frequent Alterations in the Expression of Serine/Threonine Kinases in Human Cancers

Abstract

Protein kinases constitute a large family of regulatory enzymes involved in the homeostasis of virtually every cellular process. Subversion of protein kinases has been frequently implicated in malignant transformation. Within the family, serine/threonine kinases (STK) have received comparatively lesser attention, vis-a-vis tyrosine kinases, in terms of their involvement in human cancers. Here, we report a large-scale screening of 125 STK, selected to represent all major subgroups within the subfamily, on nine different types of tumors (f200 patients), by using in situ hybridization on tissue microarrays. Twenty-one STK displayed altered levels of transcripts in tumors, frequently with a clear tumor typespecific dimension. We identified three patterns of alterations in tumors: (a) overexpression in the absence of expression in the normal tissues (10 kinases), (b) overexpression in the presence of expression by normal tissues (8 kinases), and (c) underexpression (3 kinases). Selected members of the three classes were subjected to in-depth analysis on larger case collections and showed significant correlations between their altered expression and biological and/or clinical variables. Our findings suggest that alteration in the expression of STK is a relatively frequent occurrence in human tumors. Among the overexpressed kinases, 10 were undetectable in normal controls and are therefore ideal candidates for further validation as potential targets of molecular cancer therapy.

Pirin Inhibits Cellular Senescence in Melanocytic Cells

“…20 For the preliminary screening of PIR expression in human tissues, three multitumor TMAs composed of various tumor specimens and respective normal counterparts (when available) were analyzed. Arrayed samples, provided by the Pathology departments of Ospedale Maggiore (Novara), Presidio Ospedaliero (Vimercate), and Ospedale Sacco (Milano), included breast, colon, kidney, larynx, lung, prostate, ovarian, and gastric carcinomas, as well as melanomas, lymphomas, and glial tumors.…”

Nek7 kinase targeting leads to early mortality, cytokinesis disturbance and polyploidy

“…The involvement of Nek7 in tumorigenesis is thus anticipated. Indeed, genome-wide screening revealed mutations at Nek7-coding sequence in human lung and ovary cancers (Sjoblom et al, 2006), and in situ RNA analysis on tissue microarrays demonstrated nek7 overexpression in the breast, colon and larynx cancers (Capra et al, 2006). Further studies are required to clarify the impact of Nek7 on human carcinogenesis and dissect the cytokinesis signaling pathways affected by this kinase.…”

Expression profiling of persistent polyclonal B-cell lymphocytosis suggests constitutive expression of the AP-1 transcription complex and downregulation of Fas-apoptotic and TGFβ signalling pathways

“…STK17A was recently found to be commonly downregulated in non-Hodgkin's lymphoma. 6 Letters to the Editor BACH2 is a B-cell specific transcription factor that induces apoptosis in lymphoma cells and reduced expression has been associated with poor prognostic outcome in diffuse large B-cell lymphoma. 7 Our data also suggested that many components of the transforming growth factor-b (TGFb) signalling pathway are downregulated in PPBL (Supplementary Figure S3), including the tumour-suppressor molecule SMAD4 (Figure 1i; P ¼ 0.007).…”

“…The NFIA gene, located in the 1p31 chromosomal region, has a function in brain, [2][3][4] ureteral and renal development 3 as well as hematopoiesis. 5,6 Interactions of NFIA with CEBPa and PU.1 through microRNAs regulate granulocytic and monocytic differentiation, respectively. 5,6 NFIA regulates erythropoiesis through a network involving NR2C1, GATA1 and erythropoietin.…”

“…5,6 Interactions of NFIA with CEBPa and PU.1 through microRNAs regulate granulocytic and monocytic differentiation, respectively. 5,6 NFIA regulates erythropoiesis through a network involving NR2C1, GATA1 and erythropoietin. [7][8][9] To determine whether NFIA could have a function in early leukemogenesis, we searched for alterations of the NFIA gene in 89 chronic hematopoietic diseases by using array-comparative genomic hybridization (aCGH) and DNA sequencing.…”