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Transforming growth factor‐β responsiveness in DPC4/SMAD4 ‐null cancer cells
Author(s) -
Dai Jia Le,
Schutte Mieke,
Bansal Ravi K.,
Wilentz Robb E.,
Sugar Avrahom Y.,
Kern Scott E.
Publication year - 1999
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(199909)26:1<37::aid-mc5>3.0.co;2-6
Subject(s) - biology , cancer research , carcinogenesis , transforming growth factor beta , null cell , transforming growth factor , pancreas , signal transduction , gene , tumor suppressor gene , cancer , genetics , microbiology and biotechnology , endocrinology
DPC4/SMAD4 is a candidate tumor suppressor gene with a strikingly high frequency of gene alterations in pancreatic cancer that suggests a discrete role for DPC4 in these tumors. DPC4 tumor‐suppressive function has been implicated to mediate the transforming growth factor‐β (TGFβ)–suppressive pathway; however, in a DPC4 ‐null pancreatic cancer cell line, TGFβ growth‐inhibitory and transcriptional responses were found to be DPC4 ‐independent. This was observed within native cells having a natural homozygous deletion and in clones engineered for stable expression of wild‐type DPC4 integrated into the genome. This observation contrasted with the absolute DPC4 dependence of TGFβ responses in a breast cancer cell line studied in parallel. This growth‐inhibitory response to TGFβ in DPC4 ‐null cells relied on an intact ras effector pathway. These data further suggest a major categorization of TGFβ responses into DPC4 ‐dependent and ‐independent signaling pathways and specifically suggest that disruption of the TGFβ‐independent signal might be a basis of selection for the emergence of DPC4 alterations during tumorigenesis in the pancreas and other sites. Mol. Carcinog. 26:37–43, 1999. © 1999 Wiley‐Liss, Inc.