Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation

Joan L. Cmarik, Hongzhong Min, Glenn Hegamyer, Shuning Zhan, Molly Kulesz-Martin, Hidetoshi Yoshinaga, Sachiko Matsuhashi, Nancy H. Colburn

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Abstract

An mRNA differential display comparison of mouse JB6 promotion-sensitive (P+) and -resistant (P-) cells identified a novel gene product that inhibits neoplastic transformation. The JB6 P+ and P-cells are genetic variants that differ in their transformation response to tumor promoters; P+ cells form anchorage-independent colonies that are tumorigenic, and P- cells do not. A differentially displayed fragment, A7-1, was preferentially expressed in P- cells at levels ≥10-fold those in P+ cells, making its mRNA a candidate inhibitor of neoplastic transformation. An A7-1 cDNA was isolated that was identical to murine Pdcd4 gene cDNAs, also known as MA-3 or TIS, and analogous to human H731 and 197/15a. Until now, the function of the Pdcd4 protein has been unknown. Paralleling the mRNA levels, Pdcd4 protein levels were greater in P- than in P+ cells. Pdcd4 mRNA was also expressed at greater levels in the less progressed keratinocytes of another mouse skin neoplastic progression series. To test the hypothesis that Pdcd4 inhibits tumor promoter-induced transformation, stable cell lines expressing antisense Pdcd4 were generated from parental P- cells. The reduction of Pdcd4 proteins in antisense lines was accompanied by acquisition of a transformation-sensitive (P+) phenotype. The antisense-transfected cells were reverted to their initial P-phenotype by overexpression of a Pdcd4 sense fragment. These observations demonstrate that the Pdcd4 protein inhibits neoplastic transformation.

Original languageEnglish (US)
Pages (from-to)14037-14042
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number24
DOIs
StatePublished - Nov 23 1999
Externally publishedYes

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Carcinogens
Proteins
Messenger RNA
Complementary DNA
Phenotype
Gene Expression Profiling
Keratinocytes
Genes
Cell Line
Skin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. / Cmarik, Joan L.; Min, Hongzhong; Hegamyer, Glenn; Zhan, Shuning; Kulesz-Martin, Molly; Yoshinaga, Hidetoshi; Matsuhashi, Sachiko; Colburn, Nancy H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 24, 23.11.1999, p. 14037-14042.

Research output: Contribution to journalArticle

Cmarik, Joan L. ; Min, Hongzhong ; Hegamyer, Glenn ; Zhan, Shuning ; Kulesz-Martin, Molly ; Yoshinaga, Hidetoshi ; Matsuhashi, Sachiko ; Colburn, Nancy H. / Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 24. pp. 14037-14042.
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