Reciprocal relationship between the tumor suppressors p53 and BAX in primary colorectal cancers

Abstract

Though most colorectal cancers show allelic losses, a subset of colorectal cancers (microsatellite instability or MSI-positive cancers) develop numerous small insertion and deletion mutations in repetitive DNA. Some of these sequences occur in coding regions of cancer related genes which, when targeted by frameshift mutations, produce truncations in their protein product. Such a gene is the proapoptotic tumor suppressor, BAX, mutated by frameshifts within a polyG sequence in approximately 50% of MSI-positive colorectal cancers. BAX is directly transactivated by p53, a gene commonly mutated in colorectal cancers but not often in MSI-positive lesions. Here we sought to characterize the relationship between BAX and p53 by simultaneously analysing a selected series of 65 colorectal tumors for mutations in the entire coding regions of both genes. The tumors comprised 19 MSI-high, 12 MSI-low and 34 MSI-null cancers. Eight of 19 MSI-high sporadic colorectal cancers (42%) contained insertions and deletions at the polyG tract in the BAX gene. In addition, three somatic BAX missense mutations were identi®ed in two tumors. A single missense mutation was detected in an MSI-high tumor that also contained a frameshift microdeletion, and two missense mutations were identi®ed in an MSI-null tumor wild-type for p53. p53 mutations were detected in 5/12 MSI-low tumors (42%) and 12/34 MSI-null tumors (35%). Of signi®cance, no p53 mutations were detected in MSI-high tumors. This study demonstrates that a reciprocal relationship exists between p53 and BAX in sporadic colorectal cancers, and further supports the hypothesis that MSI-low tumors are biologically similar to MSI-null tumors.

Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo

“…In this respect, the lack of a dependency on bax for p53-dependent apoptosis in these normal cells is the same as was found for normal murine thymocytes following 2.25 Gy of radiation (Knudson et al, 1995). The mutation of bax in colon carcinomas has been suggested to contribute towards the resistance of these tumours to therapy (Rampino et al, 1997;Simms et al, 1998). If this is correct, it has to be assumed from our data in normal murine cells, that either the control of expression and possibly function of bax in the human gut is di erent from the mouse and/or that changes in bax function occur during carcinogenesis.…”

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

“…This finding leads to the hypothesis that pERK is involved in the mechanism of tumor progression of MMR-proficient CRC and Lynch syndrome by interacting with the wnt signaling pathway and RHAMM: (1) KRAS mutation is found in approximately 35% of unselected CRCs, whereas it is mutated at a particularly low frequency in sporadic MSI-H cancers. [38][39][40][41][42] (2) The molecule ERK, a member of the MAPK pathway, is activated by a cascade of phophorylation events downstream from the ras proto-oncogene. 8 (3) Intracellular and cell surface RHAMM isoforms are important for the activation of ERK by PDGF (platelet-derived growth factor) and mutant (activated) RAS, respectively, while intracellular RHAMMv4 overexpression activates ERK.…”

Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐XL in addition to Bax and p53 status

“…14 Mutation in the bax gene has been reported in some colon cancers, the majority of which have a defect in DNA mismatch repair which is readily detected by mutations in repetitive sequences. 15 A reciprocal relationship has been reported between bax and p53 mutational status, 16,17 suggesting that a failure in the p53/bax pathway is of importance for colon tumor cells to escape apoptosis. The low expression of the proapototic Bax protein in most of the colon tumors has been correlated with the poor survival of patients.…”