Direct interaction with and activation of p53 by SMAR1 retards cell‐cycle progression at G₂/M phase and delays tumor growth in mice

Abstract

The tumor-suppressor p53 is a multifunctional protein mainly responsible for maintaining genomic integrity. p53 induces its tumor-suppressor activity by either causing cellcycle arrest (G 1 /S or G 2 /M) or inducing cells to undergo apoptosis. This function of wild-type p53 as "guardian of the genome" is presumably achieved by forming molecular complexes with different DNA targets as well as by interacting with a number of cellular proteins, e.g., Mdm2, Gadd45, p21, 14-3-3, Bax and Apaf-1. Upon activation, p53 activates p21, which in turn controls the cell cycle by regulating G 1 or G 2 checkpoints. Here, we report SMAR1 as one such p53-interacting protein that is involved in delaying tumor progression in vivo as well as in regulating the cell cycle. SMAR1S activates p53-mediated reporter gene expression in mouse melanoma cells, breast cancer cells (MCF-7) and p53 null cells (K562), followed by activation of its downstream effector, p21. We further demonstrate that SMAR1 physically interacts and colocalizes with p53. These data together suggest that SMAR1 is the only known MARBP that delays tumor progression via direct activation and interaction with tumor-suppressor p53.

Abnormal V(D)J Recombination of T Cell Receptor β Locus in SMAR1 Transgenic Mice

“…RT-PCR assays were done as described previously (34) except that the cDNA was amplified for 27-30 cycles (94°C for 1 min, 65°C for 1 min, 72°C for 1 min). RT-PCR products were then separated on a 1.2% agarose gel and visualized by staining with ethidium bromide.…”

“…Earlier, we reported a novel MAR-binding protein, SMAR1, interacting with MAR␤ (32), a MAR flanking 5Ј-end of the TCR␤ enhancer (E␤) (33). SMAR1 is the first known MARbinding protein that functions as a candidate tumor suppressor by interacting with and activating p53, thereby regulating the cell cycle (34).…”

Trichosanthin induced apoptosis in HL-60 cells via mitochondrial and endoplasmic reticulum stress signaling pathways

“…After washing, the 200×g centrifuged cell pellets were resuspended in 1 ml of hypotonic fluorochrome solution [propidium iodide (PI) 50 μg/ml in 0.1M sodium citrate plus 0.1% Triton X-100; Sigma (MO, USA)]. The samples were placed overnight in the dark at 4°C, and the PI fluorescence of individual nuclei measured using a FACScan flow cytometer as described [21]. According to the DNA content, an apoptotic ratio was calculated after analysis with Modfit software (DNA Modeling System).…”

Libraries enriched for alternatively spliced exons reveal splicing patterns in melanocytes and melanomas

“…The Tsc2 gene product is involved in tumor suppressor activity and is one of two genes associated with the tuberous sclerosis complex, where its GTPase-activating protein domain targets the small GTPase Rheb (Ras homologue enriched in brain) 19 . For Banp, at least two alternative splicing variants have been identified, one of which was associated with decreasing tumor growth 20 . Hps1 is involved in Hermansky-Pudlak syndrome (HPS or pale ear), which is an autosomal recessive disorder causing oculocutaneous albinism due to defective biosynthesis or processing of melanosomes, and it has been related to trafficking of tyrosinase or tyrosinase-related protein 1 (ref.…”