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Mitogen-activated protein kinases and apoptosis in PIN
C Magi-Galluzzi1, R Montironi, M G Cangi
1Department of Pathology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Mass, USA.
Abstract:
Mitogen-activated protein (MAP) kinases are key elements of the signalling systems needed to transduce different extracellular messages into cellular responses. At least three parallel MAP kinase pathways have been identified: one, stimulated by serum and growth factors to activate extracellular signal-regulated protein kinases (ERKs) by dual tyrosine and threonine phosphorylation, triggers cell proliferation or differentiation; the other two, induced by a variety of cellular stresses to activate c-jun N-terminal kinases (JNKs) and reactivating kinase (p38/RK), result in growth arrest and induction of apoptosis. Mitogen-activated protein kinase phosphatases (MKPs) inactivate MAP kinases through dephosphorylation and, thus, can modulate the MAP kinase pathways. Expression of JNK-1, ERK-1, p38/RK and MKP-1 proteins was investigated by immunohistochemistry and expression of MKP-1 mRNA by in situ hybridisation in 50 cases of high-grade prostatic intraepithelial neoplasia (PIN), thought to represent the precursor of prostate cancer. The frequency of apoptotic cells was also determined in these cases. Overexpression of the three MAP kinases and MKP-1 mRNA was found in all cases of high-grade PIN compared with normal prostate. Immunoreactivity for MKP-1 protein was found to be as intense as in normal glands in 30% and weaker in 56% of the PIN cases. Fourteen per cent of PIN cases did not stain with MKP-1 antibody. The proportion of apoptosis was significantly higher (P < 0.008) in PIN lesions that did not express MKP-1 protein than in those that did. These results are consistent with our previous demonstration of preferential inhibition of the apoptosis-related kinases by MKP-1 and further support the contention that MKP-1, even in PIN, may shift the balance existing between cell proliferation and death. When expressed, it may inhibiting those pathways that lead to apoptosis.
Insights
Mitogen-activated protein (MAP) kinases and MKP-1 are overexpressed in high-grade prostatic intraepithelial neoplasia (PIN). MKP-1 protein expression inversely correlates with apoptosis, suggesting a role in prostate cancer progression.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Cancer research
Background:
- Mitogen-activated protein (MAP) kinases are crucial for cellular responses to external signals.
- MAP kinase pathways regulate cell proliferation, differentiation, growth arrest, and apoptosis.
- Mitogen-activated protein kinase phosphatases (MKPs) modulate these pathways by dephosphorylating MAP kinases.
Purpose of the Study:
- To investigate the expression of key MAP kinases (JNK-1, ERK-1, p38/RK) and MKP-1 in high-grade prostatic intraepithelial neoplasia (PIN).
- To determine the relationship between MKP-1 expression and apoptosis in PIN lesions.
- To understand the potential role of MKP-1 in prostate cancer development.
Main Methods:
- Immunohistochemistry was used to detect JNK-1, ERK-1, p38/RK, and MKP-1 protein expression in 50 high-grade PIN cases.
- In situ hybridization was employed to assess MKP-1 mRNA levels.
- Apoptotic cell frequency was quantified in the same samples.
Main Results:
- Overexpression of JNK-1, ERK-1, p38/RK, and MKP-1 mRNA was observed in all high-grade PIN cases compared to normal prostate tissue.
- MKP-1 protein showed variable expression: intense in 30%, weaker in 56%, and absent in 14% of PIN cases.
- A significantly higher proportion of apoptosis was found in PIN lesions lacking MKP-1 protein expression (P < 0.008).
Conclusions:
- MAP kinases and MKP-1 are dysregulated in high-grade PIN, a precursor to prostate cancer.
- MKP-1 expression is inversely correlated with apoptosis in PIN.
- MKP-1 may play a role in regulating the balance between cell proliferation and apoptosis, potentially influencing prostate cancer development.