Overexpression of leukocyte marker CD43 causes activation of the tumor suppressor proteins p53 and ARF

Abstract

CD43 or leukosialin is a transmembrane sialoglycoprotein, whose extracellular domain participates in cell adhesiveness and the cytoplasmic tail regulates a variety of intracellular signal transduction pathways involved in cell proliferation. CD43 is abundantly expressed on the surface of hematopoietic cells, but CD43 expression is also frequently found in the tumor cells of nonhematopoietic origin. In the early stages of some tumors, the accumulation of tumor suppressor protein p53 has been described. Here, we show that the expression of CD43 causes the induction of functionally active p53 protein.Moreover, we found that the activation of p53 by CD43 is mediated by tumor suppressor protein ARF. The coexpression of CD43 and ARF in ARF-null mouse embryonic fibroblasts resulted in programmed cell death, but that was not the case when CD43 alone was expressed in these cells. These data provide the first evidence of the connection between p53-and CD43-dependent pathways.

Leukocyte marker CD43 promotes cell growth in co-operation with β-catenin in non-hematopoietic cancer cells

“…The latter indicates stabilization and activation of p53 probably due to the inhibition of MDM2-mediated degradation of p53 (42). Phosphorylation of serine 15 on p53 protein is induced in response to CD43 overexpression as well (34). Fig.…”

“…Human wild-type TP53 in pCG vector and human SPN in pcDNA vector have been previously described (34,39). Human CTNNB1 in pCI-neo vector encoding mutated β-catenin (S33Y) was obtained from Dr B. Vogelstein.…”

“…Western blot analysis was performed as previously described (34). The primary antibodies used were: mAb anti-CD43-4D2 (23), mAb anti-β-catenin (BD Biosciences), pAb anti-phospho p53Ser15 (Cell Signaling), mAb anti-β-actin (AC-15, Abcam), pAb anti-GRP78/BiP (Abcam), mAb anti-RNA polymerase II (4H8, Abcam) and pAb antihistone H3 (Abcam).…”

“…We have previously shown that CD43 overexpression induces the accumulation of transcriptionally active p53, and this occurs due to the stimulatory effect of CD43 on cell growth (34,35). As CD43 seems to co-operate with β-catenin in promoting colony formation, we tested whether it is also the case in p53 activation using luciferase reporter gene assay with p53-dependent MDM2 and CDKN1A promoters.…”

“…Its overexpression causes accumulation of the tumor suppressor protein p53 and induction of apoptosis which is an ARF-dependent process (34). Recently, we have shown that CD43 increases the colony formation ability of both human and mouse cells due to increased growth rate but only in the absence of either p53 or ARF in the cells.…”