Evaluation of sea-surface photosynthetically available radiation algorithms under various sky conditions and solar elevations.

In this study, we report on the performance of satellite-based photosynthetically available radiation (PAR) algorithms used in published oceanic primary production models. The performance of these algorithms was evaluated using buoy observations under clear and cloudy skies, and for the particular case of low sun angles typically encountered at high latitudes or at moderate latitudes in winter. The PAR models consisted of (i) the standard one from the NASA-Ocean Biology Processing Group (OBPG), (ii) the Gregg and Carder (GC) semi-analytical clear-sky model, and (iii) look-up-tables based on the Santa Barbara DISORT atmospheric radiative transfer (SBDART) model. Various combinations of atmospheric inputs, empirical cloud corrections, and semi-analytical irradiance models yielded a total of 13 (11 + 2 developed in this study) different PAR products, which were compared with in situ measurements collected at high frequency (15 min) at a buoy site in the Mediterranean Sea (the "BOUée pour l'acquiSition d'une Série Optique à Long termE," or, "BOUSSOLE" site). An objective ranking method applied to the algorithm results indicated that seven PAR products out of 13 were well in agreement with the in situ measurements. Specifically, the OBPG method showed the best overall performance with a root mean square difference (RMSD) (bias) of 19.7% (6.6%) and 10% (6.3%) followed by the look-up-table method with a RMSD (bias) of 25.5% (6.8%) and 9.6% (2.6%) at daily and monthly scales, respectively. Among the four methods based on clear-sky PAR empirically corrected for cloud cover, the Dobson and Smith method consistently underestimated daily PAR while the Budyko formulation overestimated daily PAR. Empirically cloud-corrected methods using cloud fraction (CF) performed better under quasi-clear skies (CF<0.3) with an RMSD (bias) of 9.7%-14.8% (3.6%-11.3%) than under partially clear to cloudy skies (0.30.7), however, all methods showed larger RMSD differences (biases) ranging between 32% and 80.6% (-54.5%-8.7%). Finally, three methods tested for low sun elevations revealed systematic overestimation, and one method showed a systematic underestimation of daily PAR, with relative RMSDs as large as 50% under all sky conditions. Under partially clear to overcast conditions all the methods underestimated PAR. Model uncertainties predominantly depend on which cloud products were used.

Mutant p53 tumor suppressor gene causes resistance to transforming growth factor beta 1 in murine keratinocytes.

Human carcinoma cell lines are frequently refractory to the antiproliferative effect of the autocrine growth inhibitor transforming growth factor beta 1 (TGF-beta 1) and often express mutant forms of the tumor suppressor gene p53. Therefore, we wished to determine whether mutant p53 affects the cellular response to TGF-beta 1. A murine p53 complementary DNA carrying an activating point mutation was introduced into TGF-beta 1-sensitive BALB/MK mouse epidermal keratinocytes by retroviral infection. Mp53 transformed cells displayed a spindle-type morphology and expressed between 0.02 and 0.7 ng of mutant p53/mg total protein. Furthermore, whereas TGF-beta 1 caused approximately 90% maximal inhibition of DNA synthesis of parental BALB/MK cells, the Mp53 transformants were inhibited by less than 70%. The median inhibiting dose of TGF-beta 1 was 4.07 +/- 1 (SE) pM for BALB/MK cells, but ranged from 2.4 to 11.2 pM and from 11.7 to 40 pM for two different sets of Mp53 transformants, and increased as a function of the amounts of mutant p53 protein that were expressed. Our findings suggest that mutant forms of p53 inhibit the antiproliferative effect of TGF-beta 1 by interfering with its signaling pathway.

Activation of the autocrine transforming growth factor alpha pathway in human squamous carcinoma cells.

Transforming growth factor alpha is an autocrine mitogen for nonneoplastic keratinocytes, which exerts its function by binding to the receptor for epidermal growth factor. In order to determine whether this autocrine pathway is activated in squamous carcinoma cells, we analyzed the production of transforming growth factor alpha as well as the expression and regulation of epidermal growth factor receptors in a panel of human squamous carcinoma cell lines. Immunoreactive transforming growth factor alpha was detectable in squamous carcinoma cells as well as in quiescent nonneoplastic keratinocytes. However, in the absence of exogenous mitogens, only the squamous carcinoma cells secreted the growth factor into the medium, whereas untransformed keratinocytes did not. Each of the squamous carcinoma cell lines expressed significantly greater numbers of cell surface epidermal growth factor receptors than normal keratinocytes. The epidermal growth factor receptor gene was amplified and overexpressed in three of the squamous carcinoma cell lines (A431, CaSki, SqCC/Y1). Two of the squamous carcinoma cell lines (C4-1 and CE-48) displayed a relative inability to down-regulate epidermal growth factor receptors in response to epidermal growth factor. The mechanism of receptor overexpression in the remaining three cell lines (A253, CaLu-1, FaDu) is unexplained. Thus, human squamous carcinoma cell lines frequently exhibit a combination of the constitutive secretion of transforming growth factor alpha and the overexpression of epidermal growth factor receptors. Treatment of these tumor cells with an antibody directed against the ligand-binding domain of the epidermal growth factor receptor inhibited their growth by approximately 50%. These findings suggest that designing strategies to interrupt the transforming growth factor alpha autocrine pathway might lead to new modalities to treat this class of malignant tumors.

Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma cells.

In this study, we report the occurrence of missense mutations of the transforming growth factor beta (TGF beta) type II receptor gene in two human squamous head and neck carcinoma cell lines. Both mutations are G:C-->C:G transversions, which result in the replacement of a glutamic acid by a glutamine, and of an arginine by a proline residue, respectively. Moreover, both are located at highly conserved sites within the serine-threonine kinase domain. One of the mutants appears to be defective in its autophosphorylation as well as in the transphosphorylation of the TGF beta type 1 receptor protein, whereas the second mutant appears to be constitutively activated. These are the first reported naturally occurring nucleotide substitution mutations in the T beta R-11 gene in human head and neck cancer cells, which may explain their resistance to TGF beta 1-mediated cell cycle arrest.

Functional characterization of transforming growth factor beta type II receptor mutants in human cancer.

We recently identified missense mutations at amino acid residues 526 and 537 located within the highly conserved subdomain XI of the transforming growth factor beta type II receptor (TbetaR-II) serine-threonine kinase in two human squamous carcinoma cell lines. These cell lines are resistant to transforming growth factor beta-mediated inhibition of growth. Moreover, treatment with transforming growth factor beta fails to increase the levels of type 1 plasminogen activator inhibitor and fibronectin synthesis. To test the effects of the mutations on receptor function, mutant TbetaR-II cDNAs were expressed in TbetaR-II-deficient T47D cells. Cyclin A promoter activity was reduced by 50% in cells expressing wild-type TbetaR-II but increased 2-fold in cells transfected with either of the two mutant receptors. Conversely, plasminogen activator inhibitor type 1 promoter activity was increased 6-fold in cells transfected with wild-type receptor but not with either of the two mutant receptors. Moreover, the activity of both mutant serine-threonine kinases was strongly reduced compared to that of the wild-type receptor. Thus, the amino acid residues at positions 526 and 537 seem to be essential for kinase function and signaling activity of the TbetaR-II.

Cloning of putative growth regulatory genes from primary human keratinocytes by subtractive hybridization.

In order to isolate genes that might be involved in regulating human keratinocyte (HKc) growth and/or differentiation, we constructed a cDNA library by subtractive hybridization between primary HKc and FaDu head-and-neck squamous cell carcinoma cells. Among the first set of independent cDNAs that we have isolated, ten correspond to known genes, and two represent novel sequences. Nine of the ten known genes are expressed at significantly lower levels in the majority of the SqCC cell lines in comparison with primary HKc. These include cDNAs that encode keratins K5 and K14 which are cytoskeletal proteins normally expressed in lining epithelia, the 14-3-3 protein stratifin/HME-1, lipocortin-II and CaN19 which are calcium-binding proteins that may play a role in HKc differentiation by regulating protein kinase C, plasminogen-activator inhibitor-2 which is a serine-proteinase inhibitor, HBp17 which is a HKc-specific secreted inhibitor of fibroblast growth factors, integrin alpha 3 which plays a role in the anchoring of keratinocytes to basement membrane, and YL-8, a ras-like protein that probably mediates intracellular protein trafficking. In addition, we isolated two cDNAs, LIS-1 which encodes the 45-kDa intracellular subunit of the platelet-activating factor acetyl-hydrolase, and the unknown sequence HFBCB84 which showed reduced expression in only a small number of tumor lines as compared to HKc. Inactivation or loss of any of these proteins may confer a selective advantage onto squamous epithelial cells and contribute to their malignant transformation.

Smad protein expression and activation in transforming growth factor-beta refractory human squamous cell carcinoma cells.

In contrast to nonneoplastic keratinocytes, human squamous carcinoma cell lines are able to proliferate in the presence of transforming growth factor-beta (TGF-beta) in vitro. This has raised the question whether, how frequently, by which mechanism, and at which stage of development squamous carcinomas escape from TGF-beta control in vivo. We have developed a method to rapidly identify the most common molecular alterations in the TGF-beta signaling pathway by combining measurements of the levels and the activation state of Smad signaling intermediates with DNA-based diagnostic assays. In this report, we demonstrate the validity of this approach using a panel of seven squamous cell carcinoma (SCC) lines known to be refractory to TGF-beta-mediated cell cycle arrest. Each of the SCCs expressed the pathway-restricted Smad proteins, Smad2 and-3. Furthermore, treatment with TGF-beta induced phosphorylation of Smad2 in each of the SCCs with the exception of the two cell lines that carry inactivating mutations of the TGF-beta type II receptor. Three of the remaining SCC lines failed to express the common mediator Smad4, two on the basis of loss of transcription and one by a posttranscriptional mechanism. Thus, a mechanism for TGF-beta resistance was identified in five of the seven tumor cell lines. Interestingly, in the two remaining lines, no abnormalities of signaling intermediates were found, and TGF-beta was able to activate TGF-beta-responsive promoters. This suggests that the ability of these two cell lines to grow in the presence of TGF-beta is due to factors extraneous to the TGF-beta pathway itself. Application of our protein-based strategy to interrogate the TGF-beta signaling pathway should allow us to determine whether or not and, if so, how and at which stage human squamous cell carcinomas become TGF-beta resistant in vivo.

Frequent inactivation of the transforming growth factor beta type II receptor in small-cell lung carcinoma cells.

Small-cell lung cancer (SCLC) has a significantly worse prognosis than other forms of bronchogenic carcinoma. Because transforming growth factor beta (TGF-beta) appears to play an important role in the pathogenesis of SCLC, we examined the status of the TGF-beta receptor system in a series of 11 human small-cell carcinoma cell lines. None of these cell lines expressed more than one-tenth the level of TGF-beta type II receptor (T beta R-II) gene mRNA produced by TGF-beta-sensitive normal epithelial cells. In addition, one of the cell lines expressed a second truncated T beta R-II transcript, which is predicted to encode a protein that lacks the terminal two-thirds of the serine-threonine kinase domain. No other structural alterations in the promoter or coding sequences of the T beta R-II gene were found in any of the cell lines, nor could the loss of T beta R-II mRNA expression be ascribed to de novo hypermethylation of promoter/enhancer sequences. These findings indicate that inactivation of the TGF-beta signaling pathway caused by the loss of T beta R-II gene expression is a common and, therefore, probably pathogenetically important feature of small-cell lung carcinoma.

Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines.

Dominant-negative and/or loss-of-function mutations of the p53 tumor suppressor gene are frequently found in squamous cell carcinomas of the skin and of the head-and-neck region. In order to identify the precise mechanisms of inactivation of p53 in tumors of this class, we examined the status of p53 RNA, protein and DNA in a panel of eight human squamous carcinoma cell lines (head-and-neck, 3; esophagus, 1; lung, 1; uterine cervix, 2; vulva, 1). Three lines (A253, CaLu-1, SqCC/Y1) failed to express any p53 mRNA. A253 cells contained a single p53 allele without mutations in exons 2-9, suggesting that the lack of transcription was the result of mutations in the regulatory region of the gene. Both p53 alleles were deleted in CaLu-1 cells, whereas the single allele present in SqCC/Y1 cells was rearranged and carried two missense mutations in exon 5. Two cell lines (A431, FaDu) expressed only 50% of the normal level of p53 mRNA, either because only one allele was present (A431), or because only one of the two alleles was transcribed (FaDu). The two cervical carcinoma lines (CaSki, C4-1) expressed normal levels of p53 mRNA, but no wild type protein, presumably as a result of accelerated degradation by the human papillomavirus 16 or -18 E6 oncoprotein present in these cells as previously described (Scheffner et al., Proc. Natl. Acad. Sci. USA 88:5523-5527; 1991). Three of the lines expressed only mutant p53 protein (A431, FaDu, CE-48) resulting from missense mutations in codons 248 and 273.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations of transforming growth factor-beta 1 receptor type II occur in ulcerative colitis-associated carcinomas, sporadic colorectal neoplasms, and esophageal carcinomas, but not in gastric neoplasms.

BACKGROUND & AIMS: Gastric cancers, sporadic colorectal cancers, and ulcerative colitis (UC)-associated colorectal carcinomas and dysplasias manifest microsatellite instability (MI); however, esophageal carcinomas rarely exhibit MI. Recently, a transforming growth factor-beta 1 type II receptor (TGF-beta 1RII) mutation in a coding microsatellite was described in primary colorectal carcinomas demonstrating MI. No previous studies of TGF-beta 1RII have addressed mechanisms of inactivation other than MI in human tumors; furthermore, MI-negative tumors have not been examined for TGF-beta 1RII mutation. We evaluated 138 primary human neoplasms for mutation in the poly-A microsatellite tract of TGF-beta 1RII. Additionally, a group of esophageal tumors was evaluated for the expression of TGF-beta 1RII messenger RNA (mRNA). METHODS: First, we determined whether MI was present at other chromosomal loci in these lesions. The poly-deoxyadenine (poly-A) microsatellite tract within the TGF-beta 1RII coding region was then PCR-amplified. In a group of MI-negative esophageal tumors, RT-PCR was performed to determine the expression of TGF-beta 1RII mRNA. RESULTS: Among 17 MI+ UC specimens, 3 (18%) demonstrated TGF-beta 1RII poly-A tract mutation (2 cancers and 1 dysplasia), while 2 (4%) of 44 MI-negative UC specimens (1 dysplasia and 1 tumor), and 13 (81%) of 16 MI+ sporadic colorectal cancers, contained TGF-beta 1RII poly-A mutation. No gastric or esophageal tumors contained TGF-beta 1RII mutation. Among 21 MI-negative esophageal carcinomas. 6 cases (28.5%) had TGF-beta 1RII transcripts that were low or undetectable by RT-PCR. CONCLUSIONS: Mutation within the poly-A microsatellite tract of TGF-beta 1RII occurs early in a subset of UC-neoplasms and commonly in sporadic colorectal cancers, but may be rare in MI+ gastric tumors. Diminished expression of TGF-beta 1RII mRNA in esophageal tumors suggests that mechanisms of inactivation in this gene other than MI play a role in esophageal carcinogenesis.

Cloning and genomic organization of the human transforming growth factor-beta type I receptor gene.

Transforming growth factor-beta (TGF beta) regulates cell cycle progression by a unique signaling mechanism that involves its binding to the type II (T beta R-II) TGF beta receptor and activation of type I (T beta R-I). Both are transmembrane serine-threonine receptor kinases. As various types of human tumor cells are often refractory to TGF beta-mediated cell cycle arrest, it is likely that the T beta R-I receptor is inactivated in many of these cases. We determined the intron-exon organization of the TGFBR1 gene. We report here that this gene is approximately 31 kb in length and consists of nine exons. The organization of the segment of the TGFBR1 gene that encodes the C-terminal portion of the serine-threonine kinase domain appears to be highly conserved between members of the R-I gene family. This information should facilitate and expedite the structural analysis of TGFBR1 in human tumors and possibly other disease states.

Wild-type p53 tumor suppressor gene restores differentiation of human squamous carcinoma cells but not the response to transforming growth factor beta.

In order to clarify the role of the p53 tumor suppressor gene in controlling growth and differentiation of human epithelial cells, we transfected a wild-type p53 complementary DNA, driven by a dexamethasone-inducible mouse mammary tumor virus promoter, into SqCC/Y1 human head-and-neck squamous carcinoma cells. When treated with dexamethasone, 2 of 8 independent clones that contained integrated vector sequences expressed wild-type p53-specific mRNA as well as nuclear p53 protein. The highest p53 expressor (SqCC/Y1.53.5) was as resistant to inhibition of cell growth by transforming growth factor beta as control transfectants. Furthermore, these cells continued to proliferate in medium containing the combination of 2 mM Ca2+ and 10% (v/v) fetal bovine serum, which normally induces terminal differentiation in primary keratinocytes. However, under these same conditions, two of the essential proteins required for the formation of the cornified cell envelope were induced. First, in SqCC/Y1.53.1 and -.5 cells, the activity of membrane-associated keratinocyte-specific transglutaminase I increased to 3- to 5-fold higher levels than in control transfectants. Second, in SqCC/Y1.53.1 and -.5 cells, the envelope precursor, involucrin, increased to 5 to 8 times the levels attained in control transfectants. Thus, reexpression of wild-type p53 does not restore responsiveness of SqCC/Y1 carcinoma cells to growth inhibition but allows cells to reexpress the proteins required for the assembly of the cornified cell envelope.

Transfer of chromosome 18 into human head and neck squamous carcinoma cells: evidence for tumor suppression by Smad4/DPC4.

Cytogenetic, allelotype, and somatic cell hybrid studies of human head and neck cancers had suggested that the long arm of chromosome 18 might carry a tumor suppressor gene locus. To directly test this hypothesis, we introduced a wild-type copy of chromosome 18 into FaDu-Hyg-R head and neck squamous carcinoma cells. Five of 10 chromosome 18 hybrid clones formed invasive carcinomas in nude mice at a significantly lower rate and after a longer latency than the parental tumor cells, whereas the five remaining clones were tumorigenic. These results indicate that tumor formation was suppressed by chromosome 18. A homozygously deleted region of 18q in FaDu-Hyg-R cells included the candidate tumor suppressor gene, Smad4/DPC4, and extended into the DCC tumor suppressor gene locus, but not Smad2/MADR2. Each of the hybrid cell lines carried a full-length donor copy of the DCC gene, independently of their capability to form tumors in vivo. In contrast, each of the hybrid clones that were either completely or partly suppressed carried an intact copy of Smad4/DPC4, whereas this gene was deleted in the two most highly tumorigenic clones. Furthermore, the presence of Smad4/DPC4 correlated with partial restoration of cellular responsiveness to transforming growth factor beta. These results provide strong evidence for tumor suppression by Smad4/DPC4.

Loss of transforming growth factor-beta type II receptor gene expression in primary human esophageal cancer.

Cell lines derived from carcinomas of the upper aero-digestive tract are typically refractory to transforming growth factor beta-mediated cell cycle arrest. Recently, we reported that the type II transforming growth factor beta receptor (T beta R-II) gene can be inactivated on the basis of missense mutations in such cell lines. These findings prompted us to investigate the molecular status of the T beta R-II gene in primary tumor specimens. Among 21 of 24 evaluable primary esophageal carcinomas, there were 6 cases (28.5%; 95% confidence interval, 11% to 52%) in which T beta R-II transcripts were low or undetectable by a reverse transcription PCR assay. In one of these cases, we were able to ascribe the loss of T beta R-II gene expression to high-density methylation of promoter sequences. We failed to detect any mutations within the open reading frame of the remaining tumors that expressed T beta R-II mRNA. In this relatively small series of cases, loss of T beta R-II expression was independent of pathologic tumor stage, histologic subtype, or outcome of patients with esophageal cancer. Thus, loss of expression of the T beta R-II gene appears to be the predominant mechanism through which this gene is inactivated in esophageal cancer.

Resistance of human squamous carcinoma cells to transforming growth factor beta 1 is a recessive trait.

Because most human squamous carcinoma cell lines of the aerodigestive and genital tracts are refractory to the antiproliferative action of transforming growth factor beta 1 (TGF beta 1) in vitro, we have begun to identify the causes for resistance of squamous carcinoma cell lines to TGF beta 1 by using somatic cell genetics. Two stable hybrid cell lines (FaDu-HKc.1 and FaDu-HKc.2) were obtained by fusing a TGF beta 1-resistant human squamous carcinoma cell line, FaDu-HygR, with a human papilloma virus 16-immortalized, TGF beta 1-sensitive, human foreskin keratinocyte cell line, HKc-neoR. Whereas TGF beta 1 did not inhibit DNA synthesis in parental FaDu-HygR cells, it reduced DNA synthetic activity of HKc-neoR, FaDu-HKc.1, and FaDu-HKc.2 cells by 75-85% (IC50, 2-5 pM). Although squamous carcinoma cells express lower than normal levels of TGF beta 1 type II receptors on their cell surface, TGF beta 1 type II receptor mRNA was detected in all four cell lines. Recessive genes involved in TGF beta 1 signaling may be localized to the distal portion of chromosome 18q, as this was the sole chromosomal region of homozygous deletion in parental FaDu-HygR cells. Furthermore, our previous observation that mutant p53 decreases sensitivity of keratinocytes to TGF beta 1 was supported by the finding that the level of the mutant p53 protein expressed by the hybrid cell lines was greatly reduced. In summary, TGF beta 1 resistance of FaDu cells appears to be recessive and is presumably due to the loss of one or more post-receptor elements of the signaling pathway.

Expression of human choriogonadotropin in monkey cells using a single simian virus 40 vector.

We have inserted the cDNAs coding for both polypeptide subunits, alpha and beta, of human choriogonadotropin (hCG) into a single simian virus 40 expression vector in such a way that they replace the viral VP2 and VP1 coding sequences, respectively. Monkey cells infected with this virus and the appropriate helper virus produce dimeric hCG. hCG produced in this system was shown to chromatograph identically to standard hCG preparations on gel filtration and to be biologically active in the mouse uterine weight assay.

Regional assignment of the erythropoietin gene to human chromosome region 7pter----q22.

The chromosomal location of the human gene for erythropoietin (EPO) was determined by Southern blot hybridization analysis of a panel of human-mouse somatic hybrid cell DNAs. DNAs from cell hybrids containing reduced numbers of human chromosomes were treated with the restriction enzyme PstI and screened with a cloned human EPO cDNA probe. EPO is assigned to human chromosome 7 based on the complete cosegregation of EPO with this chromosome in all 45 cell hybrids tested. A cell hybrid containing a translocated derivative of chromosome 7 localizes EPO to 7pter----q22. A HindIII restriction fragment length polymorphism is detected by hybridization of the EPO cDNA probe to human genomic DNA.

DNA sequence and regional assignment of the human follicle-stimulating hormone beta-subunit gene to the short arm of human chromosome 11.

A human genomic DNA fragment in phage lambda containing FSHB, the gene for the beta-subunit of human follicle-stimulating hormone (FSH-beta), was analyzed and the nucleotide sequence of the region of the clone encoding FSH-beta was determined. A subclone of the lambda phage containing 67% of FSH-beta coding sequence was used as hybridization probe to determine the human chromosomal location of FSHB. A panel of mouse-human somatic cell hybrids containing reduced numbers of human chromosomes was screened with the FSHB probe; complete cosegregation of FSHB with human chromosome 11 was observed in all 26 cell hybrids tested. Analysis of a set of cell hybrids containing translocated derivatives of chromosome 11 further localized FSHB to the human chromosome region 11p11.2----11pter. A Hind III restriction fragment length polymorphism (RFLP) detected by another subclone of the lambda phage containing FSHB now provides a genetic marker for this region of the human genome.

Structural alterations of transforming growth factor-beta receptor genes in human cervical carcinoma.

The development and progression of invasive uterine cervical carcinomas appear to be associated with the progressive loss of sensitivity to transforming growth factor-beta (TGFbeta)-mediated cell cycle arrest. In order to identify possible molecular mechanisms responsible for TGFbeta resistance, we screened the 7 exons of the type II (TbetaR-II) TGFbeta receptor and the 9 exons of the type I (TbetaR-I) TGFbeta receptor genes for mutations in 16 paraffin-embedded primary invasive cervical carcinoma specimens. In one of these carcinomas, we found a novel G-->T transversion in exon 3 of TbetaR-II that introduces a premature stop codon (E142Stop) and presumably results in the synthesis of a truncated soluble exoreceptor. In one tumor, a silent A-->C transversion mutation that may affect mRNA splicing was present in exon 6 of TbetaR-I. In addition, 7 of 16 cases were heterozygous for a G-->A polymorphism in intron 7 of TbetaR-I. Finally, we identified a 9 base pair in-frame germline deletion in exon 1 of TbetaR-I resulting in loss of 3 of 9 sequential alanine residues at the N-terminus in 6 of 16 cases. Analysis of specimens from case-control studies indicated that carriers of this del(GGC)3 TbetaR-I variant allele may be at a increased risk for the development of cervical carcinoma (p=0.22). Furthermore, the response of cells expressing the variant receptor to TGFbeta was diminished. Our results support the notion that diverse alterations in the TGFbeta signaling pathway may play a role in the development of cervical cancer.