Disease relevance of SMAD5

• However, there have been no identified mutations of SMAD5, although the gene localizes to the critical region of loss in chromosome 5q31.1 (chromosome 5, long arm, region 3, band 1, subband 1) in myelodysplasia (MDS) and acute myelogenous leukemia (AML) [1].
• Up-regulated Smad5 mediates apoptosis of gastric epithelial cells induced by Helicobacter pylori infection [2].
• Patients with secondary myelodysplasias and acute myeloid leukemias (MDS/AML) frequently exhibit interstitial deletions of the chromosome-5q resulting in hemizygous loss of the transcription transactivator Smad5 [3].
• Consistent Smad5 gene expression in these cell types and the gradual increase in its mRNA and protein levels in a model of induced erythroid differentiation of murine erythroleukemia (MEL) cells suggest a role of the gene in hematopoiesis [3].
• Analysis of the Smad5 gene in hematological malignancies [4].

High impact information on SMAD5

• Smad5 is dispensable for adult murine hematopoiesis [5].
• Here, we evaluate the role of Smad5 in the regulation of hematopoietic stem cell (HSC) fate decisions in adult mice by using an inducible MxCre-mediated conditional knockout model [5].
• Furthermore, phenotypic characterization of the stem cell compartment revealed normal numbers of primitive lin(-)Sca-1(+)c-Kit(+) (LSK) cells in Smad5(-)(/)(-) BM [5].
• More importantly, profoundly increased frequency of HPP-CFCs, featured with a gene-dosage effect, was detected within day 6 Smad5(-/-) EBs compared with the wild type [6].
• Yeast 2-hybrid interaction assays reveal the lack of physical interactions between SMAD5beta and SMAD5 or SMAD4 [1].

Biological context of SMAD5

• Absence of intragenic mutations in the remaining SMAD5 allele of leukemic patients and multiple solid tumor cell lines prescreened for loss of heterozygosity suggests that SMAD5 may not be a common target of somatic inactivation in malignancy [7].
• The findings raise the possibility that DAMS may be a fail-safe mechanism for precise regulation of SMAD5 transcript levels that may be critical in maintaining normal homeostasis [8].
• In 16 cell lines, chromosome alterations of chromosome 5 were observed in nine cell lines by fluorescence in situ hybridization (FISH), and an increase in SMAD5 gene copy number relative to the ploidy level was found in eight lines [9].
• SMAD5 gene expression, rearrangements, copy number, and amplification at fragile site FRA5C in human hepatocellular carcinoma [9].
• Collectively, our results show that SMAD5 undergoes copy number gain and increased expression, rather than loss of expression, and therefore suggest that this gene does not act as a tumor-suppressor gene in HCC [9].

Anatomical context of SMAD5

• Differential expression of a novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia [1].
• In contrast to SMAD5, DAMS expression is not readily detectable in adult and fetal tissues [8].
• We further examined whether the up-regulated Smad5 was related to apoptosis of gastric epithelial cells induced by H. pylori [2].
• METHODS: Yeast 2-hybrid technology was used to screen a complementary DNA library, constructed from human adult articular cartilage, for molecular binding partners of Smad5, a major intracellular mediator of BMP signaling [10].
• RESULTS: In the presence of BMP-2, chondrocytes over-expressing BMP-activated Smadl or Smad5 showed significant enhancement of luciferase production compared with that seen with BMP alone [11].

Associations of SMAD5 with chemical compounds

• BMP-2 caused serine phosphorylation of Smad5 as well as Smad1 [12].

Physical interactions of SMAD5

• Jun activation domain-binding protein 1 binds Smad5 and inhibits bone morphogenetic protein signaling [10].

Regulatory relationships of SMAD5

• Smad5 belongs to the receptor-activated Smad that function as intracellular signal transducers for transforming growth factor-beta superfamily [13].
• Further, individual genes, TNF-alpha induced protein 6 (TNFaip6) and membrane-spanning 4-domains, subfamily A (ms4a) were found to be upregulated in PSC while similar to Mothers against decapentaplegic homolog 5 (SMAD 5) was downregulated [14].

Other interactions of SMAD5

• In one cell line, where comparative genomic hybridization showed DNA copy number gain confined to the region 5q31, we detected by FISH high-level amplification of the SMAD5 gene located within the fragile site FRA5C [9].
• SMAD5, a transducer of TGF-beta/BMP inhibitory signals and a tumor suppressor candidate, localizes to the region of invariant loss in human myeloid neoplasms, on chromosome 5q31 [8].
• Here, we report the completion of cloning of the six known human Smads, providing novel sequences for Smad5 and Smad6 [15].
• Similarly, lefty inhibited both BMP-mediated Smad5 phosphorylation and gene transcription [16].
• Smad5 plays a key role along the bone morphogenetic protein-4 (BMP-4) inhibitory signalling pathway inducing embryonic hematopoiesis [17].

Analytical, diagnostic and therapeutic context of SMAD5

• Semiquantitative PCR suggests that the stoichiometry between SMAD5 and DAMS transcripts ranges between 15 and 120 in normal and malignant hematopoietic cells [8].
• Using confocal microscopy, we here show for the first time that immunofluorescent labeling of Smad5, one of the Smad proteins associated with BMP signaling, colocalizes with the mitochondrion-specific probe MitoTracker, demonstrating a mitochondrial distribution of Smad5 in non-stimulated chondroprogenitor cells [18].
• We showed by reverse transcriptase polymerase chain reaction that the RNA from one homologue gene, Smad5, was present in the immortalized myeloid leukemia cell lines, KG1 and HL60, in bone marrow mononuclear and polymorphonuclear cells, as well as in purified CD34+ bone marrow cells [19].

References