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(American Journal of Pathology. 1999;155:955-965.)
© 1999 American Society for Investigative Pathology


Regular Articles

Overexpression of bax Associated with Mutations in the Loop-Sheet-Helix Motif of p53

Cheng-long Huang*, Nobuoki Kohno{dagger}, Haruhiko Inufusa{ddagger}, Ken Kodama§, Toshihiko Taki* and Masayuki Miyake*

From the Department of Thoracic Surgery and Department V of Oncology,*
Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan; the Second Department of Internal Medicine,{dagger}
Ehime University School of Medicine, Ehime, Japan; the First Department of Surgery,{ddagger}
Kinki University School of Medicine, Osaka, Japan; and the Department of Surgery,§
Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

Recent investigations have revealed that mutations of the loop-sheet-helix motif of p53 is a significant factor for a poor prognosis in patients with non-small-cell lung cancer (NSCLC). To clarify this mechanism, bcl-2 and bax expression were evaluated in relation to mutations of p53. Tumor tissues of 203 patients with NSCLC were analyzed. Immunohistochemistry was performed to evaluate bcl-2 and bax expression, and polymerase chain reaction single-strand conformation polymorphism following direct sequencing was performed to investigate p53 status. A total of 79 carcinomas were bcl-2 positive, 146 carcinomas were bax positive, and 72 carcinomas had missense mutations of p53. There was no difference in bcl-2 expression in relation to p53 status. On the other hand, tumors with structural mutations of p53 had significantly lower expression of bax than those with wild-type p53 (P = 0.0026). In contrast, tumors with mutations of the loop-sheet-helix motif of p53 had significantly higher expression of bax than those with wild-type p53 (P = 0.0236). The frequency of a bcl-2/bax ratio of >=1 was significantly lower in tumors with mutations of the loop-sheet-helix motif than that in tumors with wild-type p53 (P = 0.0240). The bcl-2/bax ratio status was a significant factor for a prognosis in patients with NSCLC (P = 0.0083). Mutations of the loop-sheet-helix motif of p53 were correlated with overexpression of bax, while other mutations of p53 were correlated with low levels of bax expression. This variation in pattern of bax expression in relation to mutant p53 might reflect the biological behavior of tumors in patients with bcl-2-positive NSCLC.





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